Permanently charged sodium and calcium channel blockers as anti-inflammatory agents

ABSTRACT

The invention provides compounds, compositions, methods, and kits for the treatment of neurogenic inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No. 61/224,512, filed Jul. 10, 2009, which is hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides compounds, methods and kits for the treatment of neurogenic inflammation.

BACKGROUND OF THE INVENTION

The invention features methods and kits for the treatment of neurogenic inflammation by targeting nociceptors with drugs of low molecular weight, while minimizing effects on non-pain-sensing neurons or other types of cells. According to the method of the invention, small, hydrophilic drug molecules gain access to the intracellular compartment of pain-sensing neurons via entry through receptor/channels that are present in pain-sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue.

Neurogenic inflammation is a mode of inflammation mediated by the efferent (motor) functions of sensory neurons, in which pro-inflammatory mediator molecules released in the periphery by pain-sensing neurons (nociceptors) both activate a variety of inflammatory pathways and also act on the vascular system to alter blood flow and capillary permeability.

Neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune disease, infection, exposure to irritants in a variety of tissues, and is thought to play an important role in the pathogenesis of numerous disorders (e.g. migraine, arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn).

One way to reduce neurogenic inflammation is to block excitability in nociceptors, thereby preventing the activation of nociceptor peripheral terminals and the release of pro-inflammatory chemicals. Local anesthetics such as lidocaine and articaine act by inhibiting voltage gated ion channels in neurons. Local anesthetics are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. However, these anesthetics block sodium or calcium channels and thereby the excitability of all neurons, not just pain-sensing neurons. Thus, administration of local anesthetics produces unwanted or deleterious effects such as general numbness from block of low threshold pressure and touch receptors, motor deficits from block of motor axons and other complications from block of autonomic fibers. Local anesthetics also act on sodium channels on smooth muscle in the cardiovascular and respiratory systems producing deleterious effects.

Accordingly, there is a need for an approach to reducing neurogenic inflammation that selectively targets nociceptors.

SUMMARY OF THE INVENTION

In a first aspect, the invention features a method for treating neurogenic inflammation in a patient, such as a human, by administering a therapeutically effective amount of a compound that is capable of entering a nociceptor through a channel-forming receptor present in the nociceptor when the receptor is activated and inhibiting a voltage-gated ion channel present in the nociceptor, wherein the compound does not substantially inhibit said channel when applied to the extracellular face of the channel and when the receptor is not activated. In certain embodiments, the compound is an inhibitor of voltage-gated sodium channels. Exemplary inhibitors of this class are QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine and pancuronium. In other embodiments, the compound is a quarternary amine derivative or other charged derivative of a compound selected from riluzole, mexilitine, phenytoin, carbamazepine, procaine, articaine, bupivicaine, mepivicaine, tocainide, prilocaine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, and fluspirilene. In other embodiments, the compound is an inhibitor of calcium channels. Inhibitors of this class include D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, dodecyltrimethylammonium, and terpene compounds (e.g., sesquiterpenes), as well as charged derivatives (e.g., a quarternary amine derivative or a guanylated derivative) of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, or farnesol amine. Still other exemplary inhibitors of calcium channels can be described by Formulas XI-XIV) and in Tables 1, 2, and 3. In further embodiments, the ion channel inhibitor is a charged derivative (e.g., a quarternary amine derivative or a guanylated derivative) of any of compounds (1)-(563). Exemplary derivatives are described herein.

The channel-forming receptor can be activated prior to administering the compound by administration of a second compound that opens the channel. Alternatively, the channel-forming receptor can be activated by endogenous compounds present in the patient.

The invention also features a kit that includes a composition for treating neurogenic inflammation in a patient and instructions for the administration of the composition to a patient to treat neurogenic inflammation. The composition includes a compound that is capable of entering a nociceptor through a channel-forming receptor present in the nociceptor when the receptor is activated and inhibiting a voltage-gated ion channel present in the nociceptor, wherein the compound does not substantially inhibit said channel when applied to the extracellular face of the channel and when the receptor is not activated. In certain embodiments, the compound is an inhibitor of voltage-gated sodium channels or calcium channels, such as those described herein. In some embodiments, the compound is QX-314, N-methyl-procaine, QX-222, N-octyl-guanidine, 9-aminoacridine, pancuronium, or another low molecular weight, charged molecule that inhibits voltage-gated sodium channels when present inside of said nociceptor. In other embodiments, the compound is D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, and dodecyltrimethylammonium; a quarternary amine derivative, of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, or farnesol amine; a compound according to any of Formulas (XI), (XII), (XIII-A), (XIII-B), (XIII-C), and (XIV); or a quarternary amine derivative or other charged derivative of any of compounds (1)-(563).

Any of the compositions, methods, and kits of the invention may optionally feature a second compound that activates the channel-forming receptor. In one embodiment, the second compound activates a channel-forming receptor selected from TRPV1, P2X(2/3), TRPA1, and TRPM8.

Activators of TRPV1 receptors include but are not limited to capsaicin, eugenol, camphor, clotrimazole, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N[-2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol, oleylgingerol, oleylshogaol, SU200 (N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea), amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine. Other activators of TRPV1 receptors are described in O'Dell et al., Bioorg Med Chem. (2007) 15:6164-6149, and Sexton et al., FASEB J (2007) 21:2695-2703. Still other TRPV1 activators include black pepper compounds (e.g., Okumura et al., Biosci Biotechnol Biochem. 74(5):1068-72 (2010) and Riera et al., Br J Pharmacol. 57(8):1398-409 (2009)), terpenoids (Iwasaki et al., Life Sci. 85(1-2)60-69 (2009)), nickel (Luebbert et al., Pflugers Arch. 459(5):737-50 (2010)), SA13353 ([1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea]; see, e.g., Tsuji et al., Eur J Pharmacol. 627(1-3):332-9 (2010)), oxidized linoleic metabolites (Patwardhan et al., Proc Natl Acad Sci USA. 106(44):18820-4 (2009)), diallyl sulfides (Koizumi et al., Biochem Biophys Res Commun. 382(3):545-8 (2009)), and alkylamides derived from sanshool (Menozzi-Smarrito et al., J Agric Food Chem. 57(5):1982-9 (2009)). Activators of TRPA1 receptors include but are not limited to cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil, 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597), amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine. Other activators of TRPA1 receptors are described in Taylor-Clark et al., Mol Pharmacol (2007) PMID: 18000030; Macpherson et al., Nature (2007) 445:541-545; and Hill et al., J. Biol. Chem. (2007) 282:7145-7153. Still otherTRPA1 activators include: fenamate NSAIDS (Hu et al., Pflugers Arch. 459(4):579-92 (2010)), congeners of AP18 (Defalco et al, Bioorg Med Chem Lett. 20(1):276-9 (2010)), tear gasses CN, CR, and CS (Bröne et al., Toxicol Appl Pharmacol. 231(2):150-6 (2008)), nicotine (Talavera et al, Nat Neurosci. 12(10):1293-9 (2009)), Sichuan and Melegueta peppers (Riera et al., Br J Pharmacol. 157(8):1398-409 (2009)), diallyl sulfides nifedipine, nimodipine, nicardipine, and nitrendipine, L-type calcium channel agaonist BayK8644 (Fajardo et al., Channels (Austin) 2(6):429-38 (2008)), and isovelleral and polygodial (Escalera et al., J. Biol. Chem. 283(35):24136-44 (2008)).

Activators of P2X receptors include but are not limited to ATP, 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate).

Activators of TRPM8 receptors include but are not limited to menthol, icilin, eucalyptol, linalool, geraniol, and hydroxycitronellal.

In another aspect, the invention features compounds according to Formula (XI),

where each R^(11A), R^(11B), and R^(11C) is selected, independently, from H or C₁₋₄ alkyl, and where 0, 1, 2, or 3 of the dashed bonds represents a carbon-carbon double bond (i.e., compounds of Formula (XI) can include 0, 1, 2, or 3 double bonds), provided that when 2 or 3 carbon-carbon double bonds are present, the double bonds are not adjacent to one another. In some embodiments, compounds of Formula (XI) can be represented by the following formula (XI-A),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula (XI), and where each dashed bond represents an optional carbon-carbon double bond, or by formula (XI-B),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula (XI). In some embodiments, the compound of Formula (XI) is

In another aspect, the invention features compounds according to Formula (XII),

wherein

each of R^(12A), R^(12B), R^(12C), and R^(12D) is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; or R^(12A) and R^(12B) together complete a heterocyclic ring having at least one nitrogen atom; n is an integer between 1-5; each of R^(12E) and R^(12F) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, or C₃₋₁₀ alkheterocyclyl; and X is any pharmaceutically acceptable anion. In some embodiments, the compound has the following structure,

In another aspect, the invention features a compound having a structure according to one of the following formulas:

where each R^(13A)-R^(13J) and R^(13O)-R^(13T) is selected, independently, from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl, OR^(13AA), NR^(13AB)R^(13AC), NR^(13AD)C(O)R^(13AE), S(O)R^(13AF), SO₂R^(13AG)R^(13AH), SO₂NR^(13AI)R^(13AJ), SO₃R^(13AK), CO₂R^(13AL), C(O)R^(13AM), and C(O)NR^(13AN)R^(13AO); each of R^(13AA)-R^(13AO) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each R^(13K), R^(13L), R^(13M) and R^(13N) is, independently, H or C₁₋₄ alkyl, or R^(13K) and R^(13L), or R^(13M) and R^(13N), combine to form C═O, or R^(13K) and R^(13M) combine to form C═C; R^(13Y) is H or C₁₋₄ alkyl; R^(13Z) and R^(13Z′) are, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and X⁻ is any pharmaceutically acceptable anion. In some embodiments, the compound is selected from the group consisting of:

In another aspect, the invention features compounds according to the following formula,

where n is an integer between 0-5; R^(14A) is heterocyclyl, each of R^(14B), R^(14C), R^(14D), and R^(14E) is, independently, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and R^(14F) is selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl, OR^(14G), NR^(14H)R^(14I), NR^(14J)C(O)R^(14K), S(O)R^(14L), SO₂R^(14M)R^(14N), SO₂NR^(14O)R^(14P), SO₃R^(14Q), CO₂R^(14R) C(O)R^(14S), and C(O)NR^(14T)R^(14V); and each of R^(14G)-R^(13AO) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl. In some embodiments, the compound is

where X is a pharmaceutically acceptable anion.

The invention also features pharmaceutical compositions that include a compound according to any of Formulas (XI)-(XIV), or any of compounds (1)-(563), and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for oral, nasal, or inhalation administration.

In certain embodiments, the compounds, compositions, methods, and kits of the invention may be used to treat any disorder that is caused, wholly or in part, by neurogenic inflammation. Non-limiting examples of such disorders include asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, pancreatitis, chronic cough, sinusisitis (e.g., chronic rhinosinusistis), traumatic brain injury, sepsis (e.g., polymicrobial sepsis), tendinopathies chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants or chemical warfare agents, eczema, cystitis, gastritis, urethritis, migraine headache, psoriasis, rhinitis, rosacea, sunburn, chemical warfare agents, inhaled tear gases, or inhaled pollutants.

Some methods and kits of the invention also feature one or more acetaminophens, NSAIDs, glucocorticoids, narcotics, tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative agents, or immune modulators.

In another embodiment, the compositions are administered by intraarticular, surgical, intravenous, intramuscular, oral, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intraurethral, intravesicular, intrathecal, epidural, mucosal, aural, or ocular administration by injection, inhalation, or direct contact. In yet another embodiment, the composition is formulated for controlled or sustained release over time.

By “biologically active” is meant that a molecule, including biological molecules, such as nucleic acids, peptides, polypeptides, and proteins, exerts a physical or chemical activity on itself or other molecule. For example, a “biologically active” molecule may possess, e.g., enzymatic activity, protein binding activity (e.g., antibody interactions), or cytotoxic activities (e.g., anti-cancer properties). Biologically active agents that can be used in the methods and kits described herein include, without limitation, an antibody or antibody fragment, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.

By “inflammation” is meant any types of inflammation, such those caused by the immune system (immune-mediated inflammation) and by the nervous system (neurogenic inflammation), and any symptom of inflammation, including redness, heat, swelling, pain, and/or loss of function.

By “neurogenic inflammation” is meant any type of inflammation mediated by neurons (e.g. nociceptors) or any other component of the central or peripheral nervous system.

By “patient” is meant any animal. In one embodiment, the patient is a human. Other animals that can be treated using the methods and kits of the invention include, but are not limited to, non-human primates (e.g., monkeys, gorillas, chimpanzees), domesticated animals (e.g., horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion animals (e.g., guinea pigs, rats, mice, lizards, snakes, dogs, cats, fish, hamsters, and birds).

Compounds useful in the invention include, but are not limited to, those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, esters, amides, thioesters, solvates, and polymorphs thereof, as well as racemic mixtures and pure isomers of the compounds described herein.

By “low molecular weight” is meant less than about 650 Daltons.

The term “pharmaceutically acceptable salt” represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. These acid addition salts may also be referred to as “pharmaceutically acceptable anions.” Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

In the generic descriptions of compounds of this invention, the number of atoms of a particular type in a substituent group is generally given as a range, e.g., an alkyl group containing from 1 to 4 carbon atoms or C₁₋₄ alkyl. Reference to such a range is intended to include specific references to groups having each of the integer number of atoms within the specified range. For example, an alkyl group from 1 to 4 carbon atoms includes each of C₁, C₂, C₃, and C₄. A C₁₋₁₂ heteroalkyl, for example, includes from 1 to 12 carbon atoms in addition to one or more heteroatoms. Other numbers of atoms and other types of atoms may be indicated in a similar manner.

As used herein, the terms “alkyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e., cycloalkyl. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 6 ring carbon atoms, inclusive. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

By “C₁₋₄ alkyl” is meant a branched or unbranched hydrocarbon group having from 1 to 4 carbon atoms. A C₁₋₄ alkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C₁₋₄ alkyls include, without limitation, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and cyclobutyl.

By “C₂₋₄ alkenyl” is meant a branched or unbranched hydrocarbon group containing one or more double bonds and having from 2 to 4 carbon atoms. A C₂₋₄ alkenyl may optionally include monocyclic or polycyclic rings, in which each ring desirably has from three to six members. The C₂₋₄ alkenyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C₂₋₄ alkenyls include, without limitation, vinyl, allyl, 2-cyclopropyl-1-ethenyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, and 2-methyl-2-propenyl.

By “C₂₋₄ alkynyl” is meant a branched or unbranched hydrocarbon group containing one or more triple bonds and having from 2 to 4 carbon atoms. A C₂₋₄ alkynyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The C₂₋₄ alkynyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. C₂₋₄ alkynyls include, without limitation, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

By “C₂₋₆ heterocyclyl” is meant a stable 5- to 7-membered monocyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of 2 to 6 carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxy, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, carboxyalkyl, and carboxyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be covalently attached via any heteroatom or carbon atom which results in a stable structure, e.g., an imidazolinyl ring may be linked at either of the ring-carbon atom positions or at the nitrogen atom. A nitrogen atom in the heterocycle may optionally be quaternized. Preferably when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Heterocycles include, without limitation, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, without limitation, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, and tetrazolyl.

By “C₆₋₁₂ aryl” is meant an aromatic group having a ring system comprised of carbon atoms with conjugated π electrons (e.g., phenyl). The aryl group has from 6 to 12 carbon atoms. Aryl groups may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has five or six members. The aryl group may be substituted or unsubstituted. Exemplary substituents include alkyl, hydroxy, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, fluoroalkyl, carboxyl, hydroxyalkyl, carboxyalkyl, amino, aminoalkyl, monosubstituted amino, disubstituted amino, and quaternary amino groups.

By “C₇₋₁₄ alkaryl” is meant an alkyl substituted by an aryl group (e.g., benzyl, phenethyl, or 3,4-dichlorophenethyl) having from 7 to 14 carbon atoms.

By “C₃₋₁₀ alkcycloalkyl” is meant an alkyl substituted by a cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl) having from 3-10 carbon atoms.

By “C₃₋₁₀ alkheterocyclyl” is meant an alkyl substituted heterocyclic group having from 3 to 10 carbon atoms in addition to one or more heteroatoms (e.g., 3-furanylmethyl, 2-furanylmethyl, 3-tetrahydrofuranylmethyl, or 2-tetrahydrofuranylmethyl).

By “C₁₋₇ heteroalkyl” is meant a branched or unbranched alkyl, alkenyl, or alkynyl group having from 1 to 7 carbon atoms in addition to 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O, S, and P. Heteroalkyls include, without limitation, tertiary amines, secondary amines, ethers, thioethers, amides, thioamides, carbamates, thiocarbamates, hydrazones, imines, phosphodiesters, phosphoramidates, sulfonamides, and disulfides. A heteroalkyl may optionally include monocyclic, bicyclic, or tricyclic rings, in which each ring desirably has three to six members. The heteroalkyl group may be substituted or unsubstituted. Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio, halide, hydroxyl, fluoroalkyl, perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl, hydroxyalkyl, carboxyalkyl, and carboxyl groups. Examples of C₁₋₇ heteroalkyls include, without limitation, methoxymethyl and ethoxyethyl.

By “halide” is meant bromine, chlorine, iodine, or fluorine.

By “fluoroalkyl” is meant an alkyl group that is substituted with a fluorine atom.

By “perfluoroalkyl” is meant an alkyl group consisting of only carbon and fluorine atoms.

By “carboxyalkyl” is meant a chemical moiety with the formula —(R)—COOH, wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇ heteroalkyl.

By “hydroxyalkyl” is meant a chemical moiety with the formula —(R)—OH, wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇ heteroalkyl.

By “alkoxy” is meant a chemical substituent of the formula —OR, wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇ heteroalkyl.

By “aryloxy” is meant a chemical substituent of the formula —OR, wherein R is a C₆₋₁₂ aryl group.

By “alkylthio” is meant a chemical substituent of the formula —SR, wherein R is selected from C₁₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkheterocyclyl, or C₁₋₇ heteroalkyl.

By “arylthio” is meant a chemical substituent of the formula —SR, wherein R is a C₆₋₁₂ aryl group.

By “quaternary amino” is meant a chemical substituent of the formula —(R)—N(R′)(R″)(R′″)+, wherein R, R′, R″, and R′″ are each independently an optionally substituted alkyl, heteroalkyl, alkaryl, alkcycloalkyl, alkheterocyclyl, alkenyl, alkynyl, heteroaryl, or aryl group as described herein. R may be an alkyl group linking the quaternary amino nitrogen atom, as a substituent, to another moiety. The nitrogen atom, N, is covalently attached to four carbon atoms of the alkyl, heteroalkyl, alkaryl, alkcycloalkyl, alkheterocyclyl, alkenyl, alkynyl, heteroaryl, and/or aryl groups, resulting in a positive charge at the nitrogen atom.

By “charged moiety” is meant a moiety which gains a proton at physiological pH thereby becoming positively charged (e.g., ammonium, guanidinium, or amidinium) or a moiety that includes a net formal positive charge without protonation (e.g., quaternary ammonium). The charged moiety may be either permanently charged or transiently charged.

As used herein, the term “parent” refers to a channel blocking compound which can be modified by quaternization or guanylation of an amine nitrogen atom present in the parent compound. The quaternized and guanylated compounds are derivatives of the parent compound. The guanidyl derivatives described herein are presented in their uncharged base form. These compounds can be administered either as a salt (i.e., an acid addition salt) or in their uncharged base form, which undergoes protonation in situ to form a charged moiety.

By “therapeutically effective amount” means an amount sufficient to produce a desired result, for example, the reduction or elimination of neurogenic inflammation in a patient (e.g., a human) suffering from a condition, disease, or illness that is caused wholly or in part by neurogenic inflammation (e.g. asthma, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, psoriasis, rhinitis, rosacea, or sunburn).

Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of intravenous QX-314 (0.4 mg/kg) on the edema elicited by injection of complete Freund's adjuvant (CFA) in the rat hindpaw determined by measuring the total volume of the hindpaw by plethysmography. The degree of swelling produced by injection of CFA is reduced by administration of QX-314 reflecting reduction in neurogenic edema resulting from the blockade of nociceptors by QX314. QX-314 by itself has no effect different from administration of saline.

FIG. 2 shows the inhibition of voltage-dependent calcium channel current in a dorsal root ganglion (DRG) neuron by N-methyl-verapamil applied in the presence of capsaicin to open TRPV1 channels. Entry of the drug into the cell, and its blocking action, depends on applying the drug in the presence of capsaicin to activate the TRPV1 channels present in the neuronal membrane.

DETAILED DESCRIPTION OF THE INVENTION

The present invention features methods and kits for the treatment of neurogenic inflammation by administering a positively-charged, voltage-gated ion channel inhibitor. In embodiments of the invention, the positively-charged, voltage-gated ion channel inhibitor is administered alone or in combination with a TRP channel agonist such as capsaicinoid (e.g. capsaicin), mustard oil, or a “caine” drug (e.g., amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), or trimecaine).

Voltage-gated ion channels in pain-sensing neurons are currently of great interest in developing strategies to treat neurogenic inflammation. Blocking voltage-dependent sodium channels in nociceptors can reduce or eliminate neurogenic inflammation by preventing activation of nociceptor peripheral terminals and the release of pro-inflammatory chemicals. A limitation in designing small organic molecules that inhibit sodium channels or calcium channels is that they must be active when applied externally to the target cell. The vast majority of such externally-applied molecules are hydrophobic and can pass through cell membranes. Accordingly, such molecules will enter all cells and thus exhibit no selectivity for affecting only nociceptors.

Some inhibitors, such as the quarternary ammonium derivative QX-314, are membrane-impermeant and are only effective when present inside the nociceptor cell, and thus must pass through through the cell membrane via a channel or receptor, such as a transient receptor potential ion channel (TRP channels, e.g., TRPAV1, TRPA1, TRPM8, and P2X(2/3)), in order to produce an effect. Under normal circumstances, most TRP channels in nociceptors are not active but require a noxious thermal, mechanical, or chemical stimulus to activate them. For example, TRP channels in nociceptors can be activated by an exogenous TRP ligand (i.e. TRP agonist) such as capsaicin, which opens the TRPV1 channel. Thus, one approach to selectively targeting nociceptors is to co-administer the membrane-impermeant ion channel inhibitor with an exogenous TRP ligand that permits passage of the inhibitor through the TRP channel into the cell. In addition to capsaicin, the exogenous TRP ligand can also be another capsaicinoid, mustard oil, or lidocaine. In another example, TRP channels may be active in response to exogenous irritant activators such as inhaled acrolein from smoke or chemical warfare agents such as tear gas.

Under certain circumstances, TRP channels can be activated in the absence of exogenous TRP activators/ligands by endogenous inflammatory activators that are generated by tissue damage, infection, autoimmunity, atopy, ischemia, hypoxia, cellular stress, immune cell activation, immune mediator production, and oxidative stress. Under such conditions, endogenous molecules (e.g., protons, lipids, and reactive oxygen species) can activate TRP channels expressed on nociceptors, allowing membrane-impermeant, voltage-gated ion channel blockers to gain access to the inside of the nociceptor through the endogenously-activated TRP channels. Endogenous inflammatory activators of TRP channels include, for example, prostaglandins, nitric oxide (NO), peroxide (H₂O₂), cysteine-reactive inflammatory mediators like 4-hydroxynonenal, endogenous alkenyl aldehydes, endocannabinoids, and immune mediators (e.g., interleukin 1 (IL-1), nerve growth factor (NGF), and bradykinin).

Thus, the inventors have discovered that membrane-impermeant, positively-charged inhibitors of voltage-gated ion channels (e.g., quarternary ammonium derivatives, such as QX-314), alone or in combination with an exogenous TRP ligand, can be used to selectively target nociceptors in order to effectively treat (e.g., eliminate or alleviate) neurogenic inflammation in a patient (e.g., a human).

The invention is described in more detail below.

Neurogenic Inflammation

Inflammation is a complex set of responses to harmful stimuli that results in localized redness, swelling, and pain. Inflammation has two components, one driven by antigens and mediated by immune cells (immune-mediated inflammation) and one mediated by the nervous system (neurogenic inflammation). Neurogenic inflammation results from the efferent functions of pain-sensing neurons (nociceptors), wherein neuropeptides and other chemicals that are pro-inflammatory mediators are released from the peripheral terminals of the nociceptors when they are activated. This release process is mediated by calcium influx and exocytosis of vesicles, and the pro-inflammatory mediators include substance P, neurokinin A and B (collectively known as tachykinins), and calcitonin gene-related peptide (CGRP).

The release of peripheral terminal chemicals stimulate a variety of inflammatory responses. First, the release of substance P can result in an increase in capillary permeability such that plasma proteins leak from the intravascular compartment into the extracellular space (plasma extravasation), causing edema. This can be detected as a wheal (a firm, elevated swelling of the skin) which is one component of a triad of inflammatory responses-wheal, red spot, and flare-known as the Lewis triple response. Second, the release of CGRP causes vasodilation, leading to increased blood flow. This can be detected as a flare, which is another component of the Lewis triple response.

Substance P also has a pro-inflammatory action on immune cells (e.g. macrophages, T-cells, mast cells, and dendritic cells) via their neurokinin-1 (NK1) receptor. This effect has been documented in allergic rhinitis, gastitis, and colitis, and represents an interface between the neurogenic and immune-mediated components of inflammation. Substance P released from one nociceptor may also act on NK1 receptors on neighboring nociceptors to sensitize or activate them, causing a spread of activation and afferent/efferent function.

These efferent functions of nociceptors can be triggered by: 1) Direct activation of a nociceptor terminal by a peripheral adequate stimulus applied to the terminal (e.g. a pinch); 2) Indirect antidromic activation of a non-stimulated nociceptor terminal by the axon reflex, wherein action potential input from one terminal of a nociceptor, upon reaching a converging axonal branch point in the periphery, results in an action potential traveling from the branch point down to the peripheral terminal of a non-stimulated terminal; and 3) Activation as a result of activity in nociceptor central terminals in the CNS traveling to the periphery (e.g., primary afferent depolarization of central terminals produced by GABA can be sufficient to initiate action potentials traveling the “wrong way”).

Neurogenic Inflammatory Disorders

In certain disorders, neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune disease, infection, and exposure to irritants in soft tissue, skin, the respiratory system, joints, the urogenital and GI tract, the liver, and the brain. Neurogenic inflammatory disorders include asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, psoriasis, rhinitis, rosacea, and sunburn. pancreatitis, chronic cough, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, or chemical warfare agents, as described herein.

Asthma

Asthma is a chronic respiratory disorder that is characterized by airway obstruction, bronchial hyperresponsiveness, and bronchial inflammation. Asthma can be induced by a variety of stimuli, including natural inhaled allergens (e.g. dust mites, pollen, and mold), household organic compounds (e.g. soap, perfume, shampoo, creams, and lotions), medications, industrial chemicals, food allergies, exercise, hormonal changes, and psychological stress. Patients who chronicically suffer from asthma experience episodes of hypersensitivity to such stimuli where the bronchi contract in spasms. During an asthma episode, inflammation of the airways causes bronchoconstriction and excess mucus production, making it difficult for the patient to breathe.

Cells responsible for airway hyperresponsiveness and obstruction include sensory and motor neurons as well as epithelial and smooth muscle cells. Asthma is the result of a complex set of interactions between these cells and the immune system, particularly the T-helper-2 cells which control the inflammatory process. There is growing evidence that communication between immune cells and neurons can be mediated by neurophilins, which are produced in increased concentrations by immune cells that enter the airways in an asthmatic episode. Neurophilins modify the functional activity of neuronal function, leading to altered neuropeptide and tachykinin production that results in neurogenic inflammation. (Renz et al. Prog. Brain Res. 146:325, 2004.) TRPV1 and TRPA1 channels also contribute to the neurogenic component of allergic asthma as well as cough and rhinitis.

Arthritis

Arthritis is a group of conditions involving inflammation and damage to the joints of the body. Arthritis can have many causes, including physical trauma and aging (osteoarthritis), autoimmune disease (rheumatoid arthritis and psoriatic arthritis), infection (septic arthritis), and gout (gouty arthritis).

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally affects the joints (synovitis), characterized by destruction of articular cartilage and bending/stiffness of the joints (ankylosis), and which leads to pain and substantial loss of mobility. RA can also cause inflammation in the skin, lungs, and kidneys. About 1% of the world population develops rheumatoid arthritis, with women having a three-fold higher risk than men.

The causes of autoimmunity in RA are not fully understood, but evidence suggests the involvement of abnormal B- and T-cell activation and the release of TNF and other cytokines. There has also been a causal link between cigarette smoke and RA. Studies have suggested that neurogenic inflammation makes an important contribution to the pathogenesis of joint pain in RA. See, for example, Levine et al. (J. Immunol. 135:843s, 1985), which showed that the severity of joint injury in RA is correlated with a greater local concentration of substance P.

Colitis

Colitis is a group of chronic autoimmune disorders characterized by inflammation of the colon. Symptoms of colitis include pain, tenderness of the abdomen, fatigue, rapid weight loss, ulcers (ulcerative colitis), and gastrointestinal bleeding. Colitis can also be triggered by many foods, including alcohol, caffeine, dairy products, spicy foods, nuts, seeds, meats, refined sugar, and raw vegetables. It is known that neurogenic mechanisms are important to the inflammatory processes in colitis. For example, studies have shown that induced colitis inflammation in mice can be mitigated using NK-1 and CGRP receptor antagonists. (Nguyen et al. Canadian J. Phys. Pharm. 81:920, 2003.)

Contact Dermatitis

Contact dermatitis is the local irritation of superficial regions of the skin caused by contact with irritants or allergens. In North America, the most common causes of allergic contact dermatitis are plants such as poison ivy and poison oak.

Common causes of irritant contact dermatitis are chemicals such as harsh soaps, detergents, and cleaning products. Symptoms of contact dermatitis include rash, blisters, wheals, hives, and burning itch. The role of neurogenic inflammation in contact dermatitis has been discussed, for example, in Guy, AMA Arch. Derm. Syphilol. 66:1, 1952.

Gastritis

Gastritis refers to a collection of disorders which induce inflammation of the stomach lining. Gastritis can be caused by excessive alcohol consumption, prolonged use of NSAIDs such as aspirin or ibuprofen, and chronic infection by bacteria (primarily Helicobacter pylori). Certain autoimmune disorders can also cause gastritis. Symptoms include internal bleeding, pain (especially in the upper abdomen), vomitting, and bloating. Gastritis can also lead to increased risk of stomach cancer.

Migraine

Migraine is a neurological disorder, more common in women than in men, that is characterized by headache, nausea, and altered perception. Migraine proceeds in several phases: 1) a prodrome phase that includes fatigue, food craving, neck stiffness, altered mood, and constipation or diarrhea; 2) an aura phase that includes disturbances of vision consisting of white/multicolored flashes of lights or dazzling lines, feelings of “pins-and-needles” in the hand and arm, auditory/olfactory hallucinations, vertigo, tingling/numbness of the face, and hypersensitivity to touch; 3) a pain phase that includes a throbbing headache accompanied by nausea, vomiting, blurred vision, nasal stuffiness, diarrhea, and local edema; and 4) a postdrome phase including fatigue and feelings of “hangover.”

There are many theories about the cause of migraine. Among these is the theory that certain nerves, when irritated, release the pro-inflammatory mediators such as substance P that lead to neurogenic inflammation and associated pain.

Rhinitis

Rhinitis, known commonly as the running nose, is a disorder involving irritation and inflammation of internal nasal mucous membranes. Rhinitis is characterized by the generation of large amounts of mucus, producing running nose, nasal congestion, and post-nasal drip. According to recent estimates, more than 50 million people in the U.S. alone suffer from rhinitis yearly. Rhinitis is categoried into infective rhinitis (caused by bacterial infection), nonallergic rhinitis (caused by hormones, drugs, and foods), and allergic rhinitis (caused by immune reactions to allergens, e.g. hayfever). The role of neurogenic inflammation in the pathogenesis of rhinitis is similar to that of asthma, where enrivonmental substances enhance the immune response, leading to downstream release of substance P from neurons.

Cystitis

Cystitis is inflammation of the urinary bladder. There are several types of cystitis, including traumatic cystitis, interstitial cystitis, eosinophilic cystitis, radiation cystitis, and hemorrhagic cystitis. Interstitial cystitis, also known as painful bladder syndrome, is a disorder characterized by urination pain, urinary frequency, urgency, and pressure in the bladder. Unlike traumatic cystitis, interstitial cystitis has not been shown to be caused by bacterial infection. The cause of interstitial cystitis is unknown but has been proposed to involve neurogenic inflammation. For example, animal studies have shown that interstitial cystitis is correlated with both central and peripheral neural upregulation (Nazif et al., Urology 69:24-33 (2007)), and that acute bladder injury resulted in a significant increase in the release of substance P and CGRP (Lucioni et al., BJU Int. 101:366-370, 2008).

Additional Neurogenic Inflammatory Disorders

Additional neurogenic inflammatory disorders will be known to those skilled in the art, and include, but are not limited to sunburn, inflammatory conditions with a neurogenic component such as inflammation of blood vessels, eczema, rosacea, psoriasis, gingivitis, pancreatitis, chronic cough, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies chronic urticaria, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, or chemical warfare agents

Inhibitors of Voltage-Gated Ion Channels

Inhibitors of voltage-gated ion channels that are suitable for use in the methods and kits of the invention for the treatment of neurogenic inflammation are desirably positively-charged, hydrophilic compounds. In one embodiment, the compounds are permanently charged (i.e., have a charge that is not transient). In another embodiment, the compounds are transiently charged. Suitable inhibitors of voltage-gated sodium channels include, but are not limited to, QX-314, N-methyl-procaine (QX-222), N-octyl-guanidine, 9-aminoacridine, and pancuronium. Suitable inhibitors of voltage-gated calcium channels include, but are not limited to, D-890 (quaternary methoxyverapamil), CERM 11888 (quaternary bepridil), N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, dodecyltrimethylammonium, and other compounds as described herein (see, e.g., charged derivatives of the compounds described in Tables 1 and 2).

Additionally, there are many known inhibitors of voltage-gated ion channels that would be of a suitable size to be useful in the methods of the invention (e.g., from about 100 to 4,000 Da, 100 to 3,000 Da, 100 to 2,000 Da, 150 to 1,500 Da, or even 200 to 1,200 Da) and that have amine groups, or can be modified to contain amine groups, that can be readily modified to be charged (e.g., as positively-charged quarternary amines, or as transiently charged, e.g., guanylated, compounds). Such inhibitors include, but are not limited to, riluzole, mexilitine, phenytoin, carbamazepine, procaine, tocainide, prilocaine, diisopyramide, bencyclane, quinidine, bretylium, lifarizine, lamotrigine, flunarizine, articaine, bupivicaine, mepivicaine, and fluspirilene.

Compounds that can be used in the methods and kits of the invention for the treatment of inflammation include compounds of formulas I-X, below.

In formula I, each of R^(1A), R^(1B), and R^(1C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, OR^(1H), NR^(1I)R^(1J), NR^(1K)C(O)R^(1L), S(O)R^(1M), SO₂R^(1N)R^(1O), SO₂NR^(1P)R^(1Q), SO₃R^(1R), CO₂R^(1S), C(O)R^(1T), and C(O)NR^(1U)R^(1V); and each of R^(1H), R^(1I), R^(1J), R^(1K), R^(1L), R^(1M), R^(1N), R^(1O), R^(1P), R^(1Q), R^(1R), R^(1S), R^(1T), R^(1U), and R^(1V) is, independently, selected from from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl X¹ is selected from-CR^(1W)R^(1X),-NR^(1Y)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(1Z)—, —CO₂—, and —OC(S)—; and each of R^(1W), R^(1X), R^(1Y), and R^(1Z) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; R^(1D) is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; and each of RE, RF, and R^(G) is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; or R^(1D) and R^(1G) together complete a heterocyclic ring having at least one nitrogen atom. In a preferred embodiment, X¹ is —NHC(O)—. Exemplary compounds of formula I include methylated quaternary ammonium derivatives of anesthetic drugs, such as N-methyl lidocaine, N,N-dimethyl prilocaine, N,N,N-trimethyl tocainide, N-methyl etidocaine, N-methyl ropivacaine, N-methyl bupivacaine, N-methyl levobupivacaine, N-methyl mepivacaine. These derivatives can be prepared using methods analogous to those described in Scheme 1. Compounds of formula I include QX-314 (CAS 21306-56-9) and QX-222 (CAS 21236-55-5) (below).

In formula II, each of R^(2A), R^(2B), and R^(2C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, OR^(2I), NR^(2J)R^(2K), NR^(2L)C(O)R^(2M), S(O)R^(2N), O₂R^(2O)R^(2P), SO₂NR^(2Q)R^(2R), SO₃R^(2S), CO₂R^(2T), C(O)R^(2U), and C(O)NR^(2V)R^(2W); and each of R^(2I), R^(2J), R^(2K), R^(2L), R^(2M), R^(2N), R^(2O), R^(2P), R^(2Q), R^(2R), R^(2S), R^(2T), R^(2U), R^(2V), R^(2W) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; X² is selected from —CR^(2X)R^(2Y)—, —NR^(2Z)C(O)—,-OC(O)—, —SC(O)—, —C(O)NR^(2AA)—,-O₂—, and —OC(S)—; and each of R^(2X), R^(2Y), R^(2Z), and R^(2AA) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; R^(2D) is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; R^(2E) is H or C₁₋₄ alkyl; and each of R^(2F), R^(2G), and R^(2H) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; or R^(2F) and R^(2G) together complete a heterocyclic ring having two nitrogen atoms. Where R^(2F) and R^(2G) form a heterocyclic ring having two nitrogen atoms, the resulting guanidine group is, desirably, selected from

where R^(2H) is H or CH₃. Desirably, R^(2F) and R^(2G) combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings. In a preferred embodiment, X² is —NHC(O)—. Exemplary compounds of formula II include N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives) of anesthetic drugs, such as desethyl-N-guanidyl lidocaine, N-guanidyl prilocaine, N-guanidyl tocainide, desethyl-N-guanidyl etidocaine, desbutyl-N-guanidyl ropivacaine, desbutyl-N-guanidyl bupivacaine, desbutyl-N-guanidyl levobupivacaine, desmethyl-N-guanidyl mepivacaine. These derivatives can be prepared using methods analogous to those described in Schemes 2-5.

The guanidyl derivatives described herein (e.g., the compounds of formula II) are presented in their uncharged base form. These compounds can be administered either as a salt (i.e., an acid addition salt) or in their uncharged base form, which undergoes protonation in situ to form a charged moiety.

The synthesis of parent drugs of formulas I and II are described in the literature. See, for example, U.S. Pat. No. 2,441,498 (synthesis of lidocaine), U.S. Pat. No. 3,160,662 (synthesis of prilocaine), DE Pat. No. 2,235,745 (synthesis of tocainide), DE Pat. No. 2,162,744 (synthesis of etidocaine), PCT Publication No. WO85/00599 (synthesis of ropivacaine), U.S. Pat. No. 2,955,111 (synthesis of bupivacaine and levobupivacaine), and U.S. Pat. No. 2,799,679 (synthesis of mepivacaine).

In formula III, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(3A), R^(3B), and R^(3C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(3L), NR^(3M)R^(3N), NR^(3O) C(O)R^(3P), S(O)R^(3Q), SO₂R^(3R)R^(3S), SO₂NR^(3T)R^(3U), SO₃R^(3V), CO₂R^(3W), C(O)R^(3X), and C(O)NR^(3Y)R^(3Z); and each of R^(3L), R^(3M), R^(3N), R^(3O), R^(3P), R^(3Q), R^(3R), R^(3S), R^(3T), R^(3U), R^(3V), R^(3W), R^(3X), R^(3Y), R^(3Z) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; Y³ is selected from from —CR^(3AA)R^(3AB)—, —NR^(3AC)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(3AD)—, —O₂—, and —OC(S)—; and each of R^(3AA), R^(3AB), R^(3AC), and R^(3AD) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each of R^(3D), R^(3E), R^(3F), and R^(3G) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; each of R^(3H), R^(3J), and R^(3K) is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl. The quaternary nitrogen in formula III is identified herein as N′. Exemplary compounds of formula III include methylated quaternary ammonium derivatives of anesthetic drugs, such as N′-methyl procaine, N′-methyl proparacaine, N′-methyl allocain, N′-methyl encainide, N′-methyl procainamide, N′-methyl metoclopramide, N′-methyl stovaine, N′-methyl propoxycaine, N′-methyl chloroprocaine, N′,N′-dimethyl flecainide, and N′-methyl tetracaine. These derivatives can be prepared using methods analogous to those described in Scheme 1.

In formula IV, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(4A) and R^(4B) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(4L), NR^(4M)R^(4N), NR^(4O)C(O)R^(4P), S(O)R^(4Q), SO₂R^(4R)R^(4S), SO₂NR^(4T)R^(4U), SO₃R^(4V), CO₂R^(4W), C(O)R^(4X), and C(O)NR^(4Y)R^(4Z); and each of R^(4L), R^(4M)R^(4N), R^(4O), R^(4P), R^(4Q), R^(4R), R^(4S), R^(4T), R^(4U), R^(4V), R^(4W), R^(4X), R^(4Y), and R^(4Z) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; Y⁴ is selected from —CR^(4AA)R^(4AB)—,-NR^(4AC)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(4AD)—,-CO₂—, and —OC(S)—; and each of R^(4AA), R^(4AB), R^(4AC), and R^(4AD) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each of R^(4C), R^(4D), R^(4E), and R^(4F) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; X⁴ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and NR^(4J)R^(4K); each of R^(4J) and R^(4K) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; and each of R^(4G), R^(4H), and R^(4I) is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl. The quaternary nitrogen in formula IV is identified herein as N″. Exemplary compounds of formula III include methylated quaternary ammonium derivatives of anesthetic drugs, such as N″,N″,N″-trimethyl procaine, N″,N″,N″-trimethyl proparacaine, N″,N″,N″-trimethyl procainamide, N″,N″,N″-trimethyl metoclopramide, N″,N″,N″-trimethyl propoxycaine, N″,N″,N″-trimethyl chloroprocaine, N″,N″-dimethyl tetracaine, N″,N″,N″-trimethyl benzocaine, and N″,N″,N″-trimethyl butamben. These derivatives can be prepared using methods analogous to those described in Scheme 1.

In formula V, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(5A), R^(5B), and R^(5C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(5M), NR^(5N)R^(5O), NR^(5P)C(O)R^(5Q), S(O)R^(5R), SO₂R^(5S)R^(5T), SO₂NR^(5U)R^(5V), SO₃R^(5W), CO₂R^(5X), C(O)R^(5Y), and C(O)NR^(5Z)R^(5AA); and each of R^(5M), R^(5N), R^(5O), R^(5P), R^(5Q), R^(5R), R^(5S), R^(5T), R^(5U), R^(5V), R^(5W), R^(5X), R^(5Y), R^(5Z), and R^(5AA) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; Y⁵ is selected from —CR^(5AB)R^(5AC)—, —NR^(5AD)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(5AE)—, —CO₂—, and —OC(S)—; and each of R^(5AB), R^(5AC), R^(5AD), and R^(5AE) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each of R^(5D), R^(5E), R^(5F), and R^(5G) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; R^(5H) is H or C₁₋₄ alkyl; and each of R^(5J), R^(5K), and R^(5L) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; or R^(5J) and R^(5K) together complete a heterocyclic ring having two nitrogen atoms. Where R^(5J) and R^(5K) form a heterocyclic ring having two nitrogen atoms, the resulting guanidine group is, desirably, selected from

where R^(5L) is H or CH₃. Desirably, R^(5L) and R^(5K) combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings. The guanylated nitrogen in formula V is identified herein as N′. Exemplary compounds of formula V include N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives) of anesthetic drugs, such as such as desethyl-N′-guanidyl procaine, desethyl-N′-guanidyl proparacaine, desethyl-N′-guanidyl allocain, desmethyl-N′-guanidyl encainide, desethyl-N′-guanidyl procainamide, desethyl-N′-guanidyl metoclopramide, desmethyl-N′-guanidyl stovaine, desethyl-N′-guanidyl propoxycaine, desethyl-N′-guanidyl chloroprocaine, N′-guanidyl flecainide, and desethyl-N′-guanidyl tetracaine. These derivatives can be prepared using methods analogous to those described in Schemes 2-5.

In formula VI, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(6A) and R^(6B) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(6K), NR^(6L)R^(6M), NR^(6N)C(O)R^(6O), S(O)R^(6P), SO₂R^(6Q)R^(6R), SO₂NR^(6S)R^(6T), SO₃R^(6U), CO₂R^(6V), C(O)R^(6W), and C(O)NR^(6X)R^(6Y); and each of R^(6K), R^(6L), R^(6M), R^(6N), R^(6O), R^(6P), R^(6Q), R^(6R), R^(6S), R^(6T), R^(6U), R^(6V), R^(6W), R^(6X), and R^(6Y) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; Y⁶ is selected from —CR^(6Z)R^(6AA)—, —NR^(6AB)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(6AC)—, —CO₂—, and —OC(S)—; and each of R^(6Z), R^(6AA), R^(6AB), and R^(6AC) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each of R^(6C), R^(6D), R^(6E), and R^(6F) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; X⁶ is selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and NR^(6AD)R^(6AE); each of R^(6AD) and R^(6AE) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; R^(6G) is H or C₁₋₄ alkyl; and each of R^(6H), R^(6I), and R^(6J) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; or R^(6H) and R^(6I) together complete a heterocyclic ring having two nitrogen atoms. Where R^(6H) and R^(6I) form a heterocyclic ring having two nitrogen atoms, the resulting guanidine group is, desirably, selected from

where R^(6J) is H or CH₃. Desirably, R^(6H) and R^(6I) combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings. The guanylated nitrogen in formula V is identified herein as N″. Exemplary compounds of formula VI include N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives) of anesthetic drugs, such as such as N″-guanidyl procaine, N″-guanidyl proparacaine, N″-guanidyl procainamide, N″-guanidyl metoclopramide, N″-guanidyl propoxycaine, N″-guanidyl chloroprocaine, N″-guanidyl tetracaine, N″-guanidyl benzocaine, and N″-guanidyl butamben. These derivatives can be prepared using methods analogous to those described in Schemes 2-5.

The synthesis of parent drugs of formulas III—VI are described in the literature. See, for example, U.S. Pat. No. 812,554 (synthesis of procaine), Clinton et al., J. Am. Chem. Soc. 74:592 (1952) (synthesis of proparacaine), U.S. Pat. No. 2,689,248 (synthesis of propoxycaine), Hadicke et al., Pharm. Zentralh. 94:384 (1955) (synthesis of chloroprocaine), U.S. Pat. No. 1,889,645 (synthesis of tetracaine), Salkowski et al., Ber. 28:1921 (1895) (synthesis of benzocaine), Brill et al., J. Am. Chem. Soc. 43:1322 (1921) (synthesis of butamben), U.S. Pat. No. 3,931,195 (synthesis of encainide), Yamazaki et al., J. Pharm. Soc. Japan 73:294 (1953) (synthesis of procainamide), U.S. Pat. No. 3,177,252 (synthesis of metoclopramide), U.S. Pat. No. 3,900,481 (synthesis of flecainide), and Fourneau et al., Bull. Sci. Pharmacol. 35:273 (1928) (synthesis of stovaine), each of which is hereby incorporated by reference.

In formula VII, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(7A), R^(7B), and R^(7C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(7L), NR^(7M)R^(7N), NR^(7O)C(O)R^(7P), S(O)R^(7Q), SO₂R^(7R)R^(7S), SO₂NR^(7T)R^(7U), SO₃R^(7V), CO₂R^(7W), C(O)R^(7X), and C(O)NR^(7Y)R^(7Z); and each of R^(7L)R^(7M), R^(7N), R^(7O), R^(7P), R^(7Q), R^(7R), R^(7S), R^(7T), R^(7U), R^(7V), R^(7W), R^(7X), R^(7Y), and R^(7Z) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; X⁷ is selected from —CR^(7AA)R^(7AB)—, —NR^(7AC)C(O)—, —OC(O)—, —SC(O)—, —C(O)NR^(7AD)—, —CO₂—, and —OC(S)—; and each of R^(7AA), R^(7AB), R^(7AC), and R^(7AD) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each of R^(7D), R^(7E), R^(7F), and R^(7G) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; and each of R^(7H), R^(7J), and R^(7K) is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl. In a preferred embodiment, X⁷ is —C(O)NH—. Exemplary compounds of formula VII include methylated quaternary ammonium derivatives of anesthetic drugs, such as N′-methyl dibucaine. These derivatives can be prepared using methods analogous to those described in Scheme 1.

In formula VIII, n=0-3 and m=0-3, with (n+m)=0-6; each of R^(8A), R^(8B), and R^(8C) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, OR^(8L), NR^(8M)R^(8N), NR^(8O)C(O)R^(8P), S(O)R^(8Q), SO₂R^(8R)R^(8S), SO₂NR^(8T)R^(8U), SO₃R^(8V), CO₂R^(8W), C(O)R^(8X), and C(O)NR^(8Y)R^(8Z); and each of R^(8L), R^(8M), R^(8N), R^(8O), R^(8P), R^(8Q), R^(8R), R^(8S), R^(8T), R^(8U), R^(8V), R^(8W), R^(8X), R^(8Y), and R^(8Z) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; X⁸ is selected from —CR^(8AA)R^(8AB)—,-NR^(8AC)C(O)—,-OC(O)—, —SC(O)—, —C(O)NR^(8AD)—,-CO₂—, and —OC(S)—; and each of R^(8AA), R^(8AB), R^(8AC), and R^(8AD) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; each of R^(8D), R^(8E), R^(8F), and R^(8G) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₂₋₆ heterocyclyl, C₆₋₁₂ aryl, C₇₋₁₄ alkaryl, and C₃₋₁₀ alkheterocyclyl; R^(8H) is H or C₁₋₄ alkyl; and each of R^(8I), R^(8J), and R^(8K) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; or R^(8I) and R^(8J) together complete a heterocyclic ring having two nitrogen atoms. Where R^(8I) and R^(8J) form a heterocyclic ring having two nitrogen atoms, the resulting guanidine group is, desirably, selected from

where R^(8K) is H or CH₃. Desirably, R^(8I) and R^(8J) combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings. The guanylated nitrogen in formula V is identified herein as N′. In a preferred embodiment, X⁸ is —C(O)NH—. Exemplary compounds of formula VIII include N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives) of anesthetic drugs, such as such as desethyl-N-guanidyl dibucaine. These derivatives can be prepared using methods analogous to those described in Schemes 2-5.

In formula IX, n=0-6; each of R^(9A), R^(9B), R^(9C), R^(9D), and R^(9E) is, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, OR^(9I), NR^(9J)R^(9K), NR^(9L)C(O)R^(9M), S(O)R^(9N), SO₂R^(9O)R^(9P), SO₂NR^(9Q)R^(9R), SO₃R^(9S), CO₂R^(9T), C(O)R^(9U), and C(O)NR^(9V)R^(9W); and each of R^(9I), R^(9J), R^(9K), R^(9L), R^(9M), R^(9N), R^(9O), R^(9P), R^(9Q), R^(9R), R^(9S), R^(9T), R^(9U), R^(9V), and R^(9W) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; X⁹ is selected from-CR^(9X)R^(9Y), —O—,-S—, and —NR^(9Z)—; and each of R^(9X), R^(9Y), and R^(9Z) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl; Y⁹ is NR^(9AA)NR^(9AB)NR^(9AC) or NR^(9AD)Z⁹; each of R^(9AA), R^(9AB), and R^(9AC) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R^(9AD) is H or C₁₋₄ alkyl; Z⁹ is

and each of R^(9F), R^(9G), and R^(9H) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, or R^(9F) and R^(9G) together complete a heterocyclic ring having two nitrogen atoms. Where R^(9F) and R^(9G) form a heterocyclic ring having two nitrogen atoms, the resulting guanidine group is, desirably, selected from

where R^(9H) is H or CH₃. Desirably, R^(9F) and R^(9G) combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings. In a preferred embodiment, X⁹=−O—. Exemplary compounds of formula IX include N-guanidyl derivatives (e.g., —C(NH)NH₂ derivatives), such as N-guanidyl fluoxetine, and methylated quaternary ammonium derivatives, such as N,N-dimethyl fluoxetine. These derivatives can be prepared using methods analogous to those described in Schemes 1-5.

In formula X, W₃ is O, NH, NCH₂R^(10J), NC(O)CH₂R^(10J), CHCH₂R^(10J), C═CHR^(10J), or C═CHR^(10K); W₁-W₂ is S, O, OCHR^(10K), SCHR^(10K), N═CR^(10K), CHR^(10L)-CHR^(10K), or CR^(10L)═CR^(10K); each of R^(10A), R^(10B), R^(10C), R^(10D), R^(10E), R^(10F), R^(10G), and R^(10H) is, independently, selected from H, OH, halide, C₁₋₄ alkyl, and C₂₋₄ heteroalkyl; R^(10J) is CH₂CH₂X^(1OA) or CH(CH₃)CH₂X^(10A); R^(10L) is H or OH; R^(10K) is H, OH, or the group:

X^(10A) is NR^(10M)R^(10N)R^(10P), or NR^(10Q)X^(10C); X^(10B) is NR^(10R)R^(10S), or NX^(10C); each of R^(10M), R^(10N), R^(10P)R^(10R), and R^(10S) is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl, or R^(10R), and R^(10S) together complete a heterocyclic ring having at least one nitrogen atom; R^(10Q) is H or C₁₋₄ alkyl; X^(1OC) is

and each of R^(10T), R^(10U), and R^(10V) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, or R^(10T) and R^(10V) together complete a heterocyclic ring having two nitrogen atoms. Where R^(10T) and R^(10V) form a heterocyclic ring having two nitrogen atoms, the resulting guanidine group is, desirably, selected from

where R^(10U) is H or CH₃. Desirably, R^(10T) and R^(10V) combine to form an alkylene or alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings. Exemplary compounds of formula X include N-guanidyl derivatives (e.g.,-C(NH)NH₂ derivatives) and methylated quaternary ammonium derivatives. N-guanidyl derivatives of formula X include, without limitation, N-guanidyl amoxapine, desmethyl-N-guanidyl trimipramine, desmethyl-N-guanidyl dothiepin, desmethyl-N-guanidyl doxepin, desmethyl-N-guanidyl amitriptyline, N-guanidyl protriptyline, N-guanidyl desipramine, desmethyl-N-guanidyl clomipramine, desmethyl-N-guanidyl clozapine, desmethyl-N-guanidyl loxapine, N-guanidyl nortriptyline, desmethyl-N-guanidyl cyclobenzaprine, desmethyl-N-guanidyl cyproheptadine, desmethyl-N-guanidyl olopatadine, desmethyl-N-guanidyl promethazine, desmethyl-N-guanidyl trimeprazine, desmethyl-N-guanidyl chlorprothixene, desmethyl-N-guanidyl chlorpromazine, desmethyl-N-guanidyl propiomazine, desmethyl-N-guanidyl prochlorperazine, desmethyl-N-guanidyl thiethylperazine, desmethyl-N-guanidyl trifluoperazine, desethyl-N-guanidyl ethacizine, and desmethyl-N-guanidyl imipramine. Methylated quaternary ammonium derivatives of formula X include, without limitation, N,N-dimethyl amoxapine, N-methyl trimipramine, N-methyl dothiepin, N-methyl doxepin, N-methyl amitriptyline, N,N-dimethyl protriptyline, N,N-dimethyl desipramine, N-methyl clomipramine, N-methyl clozapine, N-methyl loxapine, N,N-dimethyl nortriptyline, N-methyl cyclobenzaprine, N-methyl cyproheptadine, N-methyl olopatadine, N-methyl promethazine, N-methyl trimeprazine, N-methyl chlorprothixene, N-methyl chlorpromazine, N-methyl propiomazine, N-methyl moricizine, N-methyl prochlorperazine, N-methyl thiethylperazine, N-methyl fluphenazine, N-methyl perphenazine, N-methyl flupenthixol, N-methyl acetophenazine, N-methyl trifluoperazine, N-methyl ethacizine, and N-methyl Ximipramine. These derivatives can be prepared using methods analogous to those described in Schemes 1-5.

Other ion channel blockers that can contain an amine nitrogen which can be guanylated or quaternized as described herein include, without limitation, orphenadrine, phenbenzamine, bepridil, pimozide, penfluridol, flunarizine, fluspirilene, propiverine, disopyramide, methadone, tolterodine, tridihexethyl salts, tripelennamine, mepyramine, brompheniramine, chlorpheniramine, dexchlorpheniramine, carbinoxamine, levomethadyl acetate, gallopamil, verapamil, devapamil, tiapamil, emopamil, dyclonine, pramoxine, lamotrigine, fendiline, mibefradil, gabapentin, amiloride, diltiazem, nifedipine, nimodipine, nitrendipine, cocaine, mexiletine, propafenone, quinidine, oxethazaine, articaine, riluzole, bencyclane, lifarizine, and strychnine. Still other ion channel blockers can be modified to incorporate a nitrogen atom suitable for quaternization or guanylation. These ion channel blockers include, without limitation, fosphenytoin, ethotoin, phenytoin, carbamazepine, oxcarbazepine, topiramate, zonisamide, and salts of valproic acid.

Examples of these channel blockers, including still other derivatives that can be quaternized or guanylated according to the methods described herein are provided in Table 1.

TABLE 1 No. Channel Blocker Exemplary References 1 orphenadrine U.S. Pat. No. 2,567,351 (see, e.g., the compounds of Examples 1-6 and the formula described at col. 1, lines 10-24). U.S. Pat. No. 2,991,225 (see, e.g., the structure shown at col. 1, line 25). 2 phenbenzamine Passalacqua et al., “Structure and (RP-2339; Classification of H₁-Antihistamines and Antergan ®), Overview of Their Activities,” in Histamine and H1-antihistamines in Allergic Disease, F. E. R. Simons, Ed., Informa Health Care (2002). 3 bepridil U.S. Pat. No. 3,962,238 (see, e.g., Formulas I-V and compounds 1-6 of Table 1). US RE30577 4 pimozide See, e.g., Janssen et al., Arzneimittel- Forsch. 18: 261, 279, 282 (1968), and Journal of Neuroscience, 22(2): 396-403 (2002) 5 penfluridol U.S. Pat. No. 3,575,990 (see, e.g., the compounds of Formula (I), claims 1-7, and Examples I-XXXIII). 6 flunarizine U.S. Pat. No. 3,773,939 (see, e.g., Formula (I) and the compound described at col. 5, line 40). 7 fluspirilene U.S. Pat. No. 3,238,216 (see, e.g., the compounds recited in any of claims 1-34). 8 propiverine DD 106643 9 disopyramide U.S. Pat. No. 3,225,054 (see, e.g., the compounds of Examples 1-15 and claims 1-3) 10 methadone DE711069 U.S. Pat. No. 2,983,757 11 tolterodine U.S. Pat. No. 5,382,600 (see, e.g., Formula (I), the compounds described at col. 3, lines 20-39, in Table 1, and in claims 1-7) 12 tridihexethyl salts U.S. Pat. No. 2,913,494 (see, e.g., col. 1, lines 15-22) 13 tripelennamine U.S. Pat. No. 2,502,151 (see, e.g., Formula (I) and the compounds recited in claims 1-13) 14 mepyramine U.S. Pat. No. 2,502,151 (pyrilamine) 15 brompheniramine U.S. Pat. No. 2,567,245 (see, e.g., the formula described at col. 1, lines 30-45, the compounds of Examples I-XXI, and the compounds recited in claims 1-15) U.S. Pat. No. 2,676,964 (see, e.g., the formula described at col. 1, lines 5-28, the compounds of Examples I-XLIV, and the compounds recited in claims 1-14) U.S. Pat. No. 3,061,517 (see, e.g., the formula at col. 1, lines 49-67, and the compounds described at col. 2, lines 17- 19, col. 2, lines 40-43, col. 4, lines 2-7, and claims 1-6) 16 chlorpheniramine U.S. Pat. No. 2,567,245 (see, e.g., the formula described at col. 1, lines 30-45, the compounds of Examples I-XXI, and the compounds recited in claims 1-15) 17 dexchlorphen- U.S. Pat. No. 2,676,964 (see, e.g., the iramine formula described at col. 1, lines 5-28, the compounds of Examples I-XLIV, and the compounds recited in claims 1-14) U.S. Pat. No. 3,061,517 (see, e.g., the formula at col. 1, lines 49-67, and the compounds described at col. 2, lines 17- 19, col. 2, lines 40-43, col. 4, lines 2-7, and claims 1-6)U.S. Pat. No. 2,766,174 (see, e.g., the formula described at col. 1, lines 41-72) 18 carbinoxamine U.S. Pat. No. 2,606,195 (see, e.g., the formula described at col. 1, lines 7-24, Examples I-VIII, and in claims 1-3) U.S. Pat. No. 2,800,485 GB 905993 19 levomethadyl Pohland et al., J. Am. Chem. Soc. 71: 460 acetate (1949) 20 gallopamil U.S. Pat. No. 3,261,859 (see, e.g., Formula (I), Examples 1-28, and claims 1- 19) Theodore et al., J. Org. Chem. 52: 1309 (1987) 21 verapamil U.S. Pat. No. 3,261,859 (see, e.g., Formulas (I) and (IV), Examples 1-28, and claims 1-19) 22 devapamil Godfraind, Calcium Channel Blockers, 23 tiapamil Birkhauser Verlag (January 2004). 24 emopamil 25 dyclonine Pofft, Chem. Tech. (Berlin) 4: 241 (1952) 26 pramoxine U.S. Pat. No. 2,870,151 (see, e.g., the formula described at col. 1, lines 18-25, and the compounds of Examples I-XII and claims 1-13). 27 lamotrigine EP21121 U.S. Pat. No. 4,602,017 (see, e.g., Formulas (I)-(III) and the compounds described at col. 2, line 63-col. 3, line 12, Examples 1-5, and claims 1-2) 28 mibefradil U.S. Pat. No. 4,808,605 (see, e.g., Formula I described at col. 1, lines 10-33 and the compounds described at col. 3, line 58-col. 7, line 6, Examples 1-41, and claims 1-15). 29 gabapentin U.S. Pat. No. 4,024,175 (see, e.g., Formula (I) described at col. 1, lines 5-17, Examples 1-12, and claims 1-11) 30 amiloride U.S. Pat. No. 3,313,813 (see, e.g., the compounds described at col. 1, line 13- col. 2, line 55, Examples 1-205, and claims 1-31) 31 diltiazem U.S. Pat. No. 3,562,257 (see, e.g., Formula (I) described at col. 1, lines 39-64, and the compounds described at col. 2, lines 15-30, Tables 1-3, and claims 1-43) U.S. Pat. No. 4,552,695 (see, e.g., the compound of Formula (I)) 32 nifedipine U.S. Pat. No. 3,485,847 (see, e.g., the Formula described at col. 1, line 40-col. 2, line 6, the compounds of Examples 1-6, and claims 1-27) 33 nimodipine U.S. Pat. No. 3,799,934 (see, e.g., the Formula described at col. 1, lines 39-69, the compounds described at col. 4, line 50- col. 5, line 16, Examples 1-53, and claims 1-13) 34 nitrendipine 35 mexiletine U.S. Pat. No. 3,954,872 (see, e.g., Formula (I) described at col. 1, lines 14-35, and the compounds of Examples 1-6 and claims 1-4) 36 propafenone DE2001431 (see, e.g., claims 1-4) 37 quinidine Turner et al., The Alkaloids, Vol. 3, 1-63 (1953) Mason et al., Ann. N.Y. Acad. Sci. 432: 162-176 (1984) 38 oxethazaine U.S. Pat. No. 2,780,646 (see, e.g., the formula described at col. 1, lines 18-42, and the compounds of Examples 1-14 and claims 1-8) 39 articaine Becker et al., Anesth Prog. 53(3): 98-109 (Fall 2006) 40 riluzole U.S. Pat. No. 4,370,338 (see, e.g., the compound described at col. 1, line 15) 41 bencyclane HU 151865 42 lifarizine Grauert et al., J. Med. Chem. 45(17): 3755- 3764 (2002) 43 strychnine Makarevich et al., “Quaternary salts of alkaloids,” Vol. 42, pages 473-476, Chemistry of Natural Compounds, Springer New York: 2006. 44 fendiline U.S. Pat. No. 3,262,977 (see, e.g., Formula (I), Examples 1-9, and the compounds of claims 1-9)

Calcium-Channel Blockers

Exemplary cationic calcium channel blockers include D-890, CERM 11888, N-methyl-verapamil, N-methylgallopamil, N-methyl-devapamil, and dodecyltrimethylammonium. Other exemplary compounds include any charged derivative, e.g., a quarternary amine derivative, of verapamil, gallopamil, devapamil, diltiazem, fendiline, mibefradil, terpene compounds (e.g., sesquiterpenes) such as those described in Norman et al. Agricultural and Biological Chemistry 49(10):2893-8 (1985), and other inhibitors of calcium channels (see, for example, Triggle, European Journal of Pharmacology, 375:311-325 (1999), Eller et al., British Journal of Pharmacology, 130:669-677 (2000), and Yamamoto et al., Current Topics in Medicinal Chemistry, 9:377-395 (2009), which can be prepared according to the methods described herein.

For example, Yamamoto et al. provides the following N-type calcium channel blockers (Table 2), which can be modified (e.g., quaternized or guanylated) according to the methods described herein.

TABLE 2 No. Channel Blocker Exemplary References 45

Yamamoto et al., Bioorg. Med. Chem.14:5333-5339 (2006). 46

Yamamoto et al., Bioorg. Med. Chem. Lett.16:798-802 (2006). 47

Yamamoto et al., Bioorg. Med. Chem. Lett. 18:4813- 4815 (2008). 48

See, e.g., WO08143263and EP2149560 (e.g., Formula (I), the compounds of Tables 6- 35, 43-110, 126-127, and the compounds of claims 1-6) 49

Miller et al., Soc. Neurosci. Abstr. 25(Part 2):896.3 (1999) 50

WO0236567 (see, e.g., formulas I-IV, the compounds of Table 2 (Examples 1-111), and claims 1-5) 51

Zhang et al., Eur. J. Pharmacol. 587:24-47 (2008) 52

Baell et al., Bioorg. Med. Chem. 12:4025-4037 (2004) 53

Yamamoto et al., 22 ^(nd) National Meeting of American Chemical Society, American Chemical Scoiety: Washington, DC: Chicago, IL 2001; Kaneda et al, Soc. Neurosci. Abstr. 27:332.15 (2001); Niidome et al., Soc. Neurosci. Abstr. 27:332.14 (2001); and Suzuki et al., Bioorg. Med. Chem. Lett. 13:919-922 (2003). 54 E-2051 Kaneda, Soc. Neurosci. Abstr. 28:490.1 (2002) 55

WO07110449 (see, e.g., Formulas I-XIII, the compounds described at Paragraphs [0181]-[0183] and Examples 1-14, and claims 1- 72) 56

WO06040181 (see, e.g., Formulas I-X, the compounds described at Paragraphs [0105]-[0109] and Examples 1-37, and in claims 1-56) 57

WO07118853 (see, e.g., Formulas I-XIII, the compounds described at Paragraph [0320] and Examples 1-19, and the compounds of claims 1-165) 58

WO07085357 (see, e.g., Formulas I-VII, the compounds described at Paragraphs [0065]-[0067], Examples 1-6, and claims 1- 16) 59

WO07028638 (see, e.g., Formulas I-XXVI, the compounds described at Paragraphs [0119]-[0123], Examples 1-24, and claims 1-20

60

WO07118854 (see, e.g., Formulas I-VII and the compounds of Examples 1-11 and claims 1-36) 61

WO08008398 (see, e.g., Formulas I, I′, I″, II, and II′; Examples 1-377, and claims 1-7) 62

WO08150447 (see, e.g., Formulas I, I′, I″, and the compounds of Examples 1- 135 and claims 1-5 63

Knutsen et al., Bioorg. Med. Chem. Lett. 17: 662-667 (2007) 64

O'Neill, Brain Res. 888:138- 149 (2001); Hicks et al., Eur. J. Pharmacol. 408:241-248 (2000) 65

WO07084394 (see, e.g., the compounds of Formulas I and Ia-Ig, and the compounds of Examples 1-11 and claims 1 and 2) 66

WO08066803 (see, e.g., Formulas I and II, the compound of Example 1, and claims 1-11) 67

WO07075524 (see, e.g., Formulas (I), (Ia)-(Ie), the compounds of Examples 1- 184, and claims 1-16) 68

WO08133867 (see, e.g., Formulas (I) and (II), the compounds of Examples 1-163, and claims 1-16) 69

WO01045709 (see, e.g., Formula (1), the compounds of Example 4, and claims 24- 38) WO06105670 (see, e.g., Formula (1), the compounds described at Paragraphs [0065] and [0066], and claims 1-13) 70

WO04089377 (see, e.g., Formula (1), Examples 1-5, original claims 1-13, and amended claims 1-17) 71

WO07071035 (see, e.g., Formula (1), the compounds of Examples 1-18, and claims 20-35) 72

WO08043183 (see, e.g., Formulas (1) and (2), the compounds of Examples 1-16, and claims 16-28) 73

WO04089922 (see, e.g., Formulas (1)-(4), the compounds of Examples 1-9, claims 1-17, and the compounds of Figure 1) 74

WO04105750 (see, e.g., Formulas (1)-(8), the compounds of Examples 1-10, claims 1-23, and Figure 1) 75

WO08031227 (see, e.g., Formulas (1) and (2), the compounds of Examples 1-20, and claims 21-37) 76

Tatsumi et al., Jpn. J. Pharmacol. 73:193 (1997); Aoki et al., Brain Res. 890:162-169 (2001); Katsumata et al., Brain Res. 969:168-174 (2003); Tamura et al., Brain Res. 890:170-176 (2001); Shi et al., J. Thorac. Cardiovasc. Surg. 129:364- 371 (2005); Small, IDrugs, 3:460-465 (2000); Suma et al., Jpn. J. Pharmacol. 73: 193 (1997); Shimidzu et al., Naunyn Schmiedebergs Arch. Pharamcol. 355:601-608 (1997); and Suma et al., Eur. J. Pharmacol. 336:283-290 (1997). 77

Seko et al, Bioorg. Med. Chem. Lett. 11:2067-2070 (2001) 78

Seko et al., Bioorg. Med. Chem. 11:1901-1913 (2003). Seko et al., Bioorg. Med. Chem. Lett. 12:915-918 (2002) 79

Seko et al., Bioorg. Med. Chem. Lett. 12:2267-2269 (2002) 80

Menzler et al., Bioorg. Med. Chem. Lett. 10:345-347 (2000) 81

Malone et al., 217 ^(th) National Meeting of the American Chemical Society, American Chemical Society: Washington DC: Anaheim CA 1999; Hu et al., J. Med. Chem. 42:4239-4249 (1999) 82

Hu et al., Bioorg. Med. Chem. Lett. 9:907-912 (1999) 83

Hu et al., Bioorg. Med. Chem. Lett. 9:2151-2156 (1999) Ryder et al., Bioorg. Med. Chem. Lett. 9:1813-1818 (1999) 84

Hu et al., Bioorg. Med. Chem. Lett. 9:1121-1126 (1999) 85

Bennett et al., Pain 33:87-107 (1988) 86

Hu et al., Bioorg. Med. Chem. 8:1203-1212 (2000) 87

Hu et al., Bioorg. Med. Chem. 8:1203-1212 (2000) 88

Hu et al., J. Med. Chem. 42:4239-4249 (1999) 89

Schelkun et al., Bioorg. Med. Chem. Lett. 9:2447-2452 (1999). 90

Yuen et al., Bioorg. Med. Chem. Lett. 8:2415-2418 (1998) 91

Song et al., J. Med. Chem. 43:3474-3477 (2000) 92

WO07125398 (see, e.g., Formula (I), the compounds of Examples 1-29, and claims 1-9) 93

WO08124118 (see, e.g., Formula I-VI, the compounds of Paragraphs [0129] and Examples 1-5, and claims 1- 42) 94

Campbell et al., Eur. J. Pharmacol. 401:419-428 (2000) 95

Teodori et al., J. Med. Chem. 47:6070-6081 (2004) 96

Teodori et al., J. Med. Chem. 47:6070-6081 (2004) 97

Schroeder et al., Mol. Divers. 8:127-134 (2004). 98

WO06030211 (see, e.g., Formula (I), the compounds described at page 9, line 17- page 15, line 12, Examples 1- 99, and claims 1-12)

indicates data missing or illegible when filed

Farnesyl Amine Compounds

Compounds having a structure according to Formula (XI) can also be used in the invention as calcium channel blockers.

where each R^(11A), R^(11B), and R^(11C) is selected, independently, from H or C₁₋₄ alkyl, and where 0, 1, 2, or 3 of the dashed bonds represents a carbon-carbon double bond (i.e., compounds of Formula (XI) can include 0, 1, 2, or 3 double bonds), provided that when 2 or 3 carbon-carbon double bonds are present, the double bonds are not adjacent to one another. Compounds that include 0, 1, or 2 double bonds can be prepared according to methods known in the literature, e.g., partial or total hydrogenation of the parent triene.

In some embodiments, compounds of Formula (XI) can be represented by the following formula (XI-A),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula (XI), and where each dashed bond represents an optional carbon-carbon double bond. Still other farnesyl amine compounds can include those compounds that have a structure according to Formula (XI-B),

where each R^(11A), R^(11B), R^(11C), and X is according to Formula (XI).

Exemplary compounds of Formula (XI) include

Cysteine-Derived Compounds

Amino acid derivatives, e.g., those described in U.S. Pat. No. 7,166,590 or in Seko et al., Bioorg. Med. Chem. Lett. 11(16):2067-2070 (2001), each of which is herein incorporated by reference, can also be used in the invention. For example, compounds having a structure according to Formula (XII) can be N-type calcium channel blockers.

wherein each of R^(12A), R^(12B), R^(12C), and R^(12D) is, independently, selected from C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; or R^(12A) and R^(12B) together complete a heterocyclic ring having at least one nitrogen atom, n is an integer between 1-5, each of R^(12E) and R^(12F) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, or C₃₋₁₀ alkheterocyclyl, and X is any pharmaceutically acceptable anion.

Exemplary compounds of Formula (XII) include

Flunarizine and Related Compounds

Still other compounds that can be used in the invention are charged derivatives of flunarizine and related compounds (see, e.g., U.S. Pat. Nos. 2,883,271 and 3,773,939, as well as Zamponi et al., Bioorg. Med. Chem. Lett. 19: 6467 (2009)), each of which is hereby incorporated by reference. For example, compounds according to Formulas (XIII-A), (XIII-B), and (XIII-C) can be prepared according to, e.g., Zamponi et al., and used in the invention,

where each R^(13A)-R^(13J) and R^(13O)-R^(13T) is selected, independently, from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl, OR^(13AA), NR^(13AB)R^(13AC), NR^(13AD)C(O)R^(13AE), S(O)R^(13AF), SO₂R^(13AG)R^(13AH), SO₂NR^(13AI)R^(13AJ), O₃R^(13AK), CO₂R^(13AL), C(O)R^(13AM), and C(O)NR^(13AN)R^(13AO); and each of R^(13AA)-R^(13AO) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl;

each R^(13K), R^(13L), R^(13M), and R^(13N) is, independently, H or C₁₋₄ alkyl, or R^(13K) and R^(13L), or R^(13M) and R^(13N), combine to form C═O, or R^(13K) and R^(13M) combine to form C═C;

R^(13Y) is H or C₁₋₄ alkyl;

R^(13Z) and R^(13Z′) are, independently, selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and

X⁻ is any pharmaceutically acceptable anion.

Exemplary compounds according to Formulas (XIII-A)-(XIII-C) include

Mibefradil Derivatives

Derivatives of mibrefradil, such as those described in U.S. Pat. No. 4,808,605, hereby incorporated by reference can also be used. Exemplary mibrefadil derivatives include compounds of Formula (XIV),

n is an integer between 0-5;

R^(14A) is heterocyclyl (e.g., a heteroaryl such as benzimidazole), each of R^(14B), R^(14C), R^(14D), and R^(14E) is, independently, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl; and

R^(14F) is selected from H, halogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₂₋₄ heteroalkyl, C₇₋₁₄ alkaryl, C₃₋₁₀ alkcycloalkyl, and C₃₋₁₀ alkheterocyclyl, OR^(14G)NR^(14H)R^(14I), NR^(14J)C(O)R^(14K), S(O)R^(14L), SO₂R^(14M)R^(14N), SO₂NR^(14O)OR^(14P), SO₃R^(14Q), CO₂R^(14R), C(O)R^(14S), and C(O)NR^(14T)R^(14V); and each of R^(14G)-R^(13AO) is, independently, selected from H, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₂₋₄ heteroalkyl.

An exemplary compound of Formula (XIV) is

4-Piperidinylaniline Compounds

Charged derivatives of 4-piperidinylaniline compounds (e.g., Compounds (86)-(88) of Table 2) can be prepared according to methods known in the literature and described herein. For example, charged N-alkyl derivatives (e.g., N-methyl) of Compounds (86)-(88) can be prepared and used in the compositions, methods, and kits described herein.

Still other channel blockers that can be quaternized or guanylated according to the methods described herein are described, for example, in PCT Publication No. WO 2004/093813 (see, e.g., Tables 5, 6 and 8), which is herein incorporated by reference. For example, the channel blockers shown in Table 3 can be quaternized or guanylated as described herein.

TABLE 3 No. Channel Blocker Exemplary References 105 Isradipine 106 Nickel Chloride 107 A-53930A JP 08208690 108 AE-0047 Watanidipine EP 00424901 dihydrochloride 109 AGN-190604 Inflammation, 19(2): 261-275 (1995) 110 AGN-190744 EP372940 111 AH-1058 European Journal of Pharmacology, 398(1): 107-112 (2000) 112 AHR 5360C European Journal of Pharmacology 146(2-3): 215-22 (1988) 113 AHR 12234 Archives Internationales de Pharamcodynamie et de Therapie 301: 131-50 (1989) 114 AHR-12742 ZA 08604522 115 AHR-16303B Journal of Cardiovascular Pharmacology 17(1): 134-44 (1991) 116 AHR-16462B Drug Development Research, 22(3): 259-271 (1991) 117 AIT 110 118 AIT 111 119 AJ 2615 WO 8601203 A1 120 AJ-3941 Arzneimittel Forschung 46(6): 567-71 (1996) 121 (+)-alismol JP 04077420 A2 122 AM-336 (synthetic version of WO9954350 CVID marine cone snail venom) 123 AM 543 124 amlodipine U.S. Pat. No. 4,572,902 125 S-(−)amlodipine GB 2233974 A1 126 AN 132 EP 196648 127 animpamil LU 42668 EP 64158 A1 128 antioquine (alkaloid from stem Journal of natural Products bark) 55(9): 1281-6 (1992) 129 AP-1067 IDDB 268934 130 AQ-AH-208 CH 645628 A 131 AR 12456 (derivative of BE 902218 A1 trapidil) Cardiovascular Drug Reviews 9(4): 385-397 (1991) 132 aranidipine U.S. Pat. No. 4,446,325 133 atosiban EP 00112809 134 azenidipine CS 905 EP 88266922 135 B 84439 EP 240828 136 barnidipine (derivative of U.S. Pat. No. 4,220,649 nicardipine) DE 02904552 137 BAY-E-6927 DE 2117571 138 BAY-K-9320 EP 9206 139 BAY-T-7207 140 BBR-2160 EP 28204 A2 141 BDF 8784 EP 25111 142 belfosdil/BMY 21891/SR7037 EP 173041 A1 143 Bencylcalne/EGYT-201 FR 151193 144 benipidine/KW3049/N akadipine U.S. Pat. No. 4,448,964 145 bepridil U.S. Pat. No. 3,962,238 146 bisaramil/RGH 2957 WO 9622096 147 BK 129 Methods and Findings in Experimental and Clinical Pharamcology 14(3): 175-81 (1992) 148 BMS-181102 EP 559569 149 BMS-188107 U.S. Pat. No. 5,070,088 150 BMY 20014 DE 3512995 A1 151 BMY 20064 DE 3512995 A1 152 BMY-43011 Bioorganic and Medicinal Chemistry Letters, 3(12): 2817- 2820 (1993) 153 BN 50149 WO 9323082 154 BN 50175 WO 9323082 155 BN 50394 WO 9323082 156 BR 1022 Current Science 83(4): 426-431 (2002) 157 BRL 3287A WO 9323082 158 BRL-32872 WO 09323024 159 buflomedil U.S. Pat. No. 4,326,083 160 butoprozine DE 2707048 161 CAF 603 Organic and Bioorganic Chemistry, 22: 3349: 52 (1994) 162 calciseptine (venom WO 2000 069900 polypeptide) 163 calcium antagonists WO 9205165 164 calcium channel antagonists WO 00236586 WO 0236567 165 calcium channel blocker (L- Journal of Medicinal Chemistry, type) 39(15): 2922-2938 (1996) 166 calcium channel blockers EP 400665 A2 U.S. Pat. No. 4,965,356 167 calcium channel blockers WO 9526325 168 carvedilol U.S. Pat. No. 4,503,067 169 caryachine British Journal of Pharmacology, 116(8): 3211-8 (1995) 170 CD-349 EP 92936 A1 171 CD-832 EP 00370821 172 CER-2 metabolite of furnipidine WO 9919302 173 cerebrocrast DE 3534385 174 CERM 11956 EP 138684 175 CERM-12816 IDDB 283075 176 CGP 22442 WO 9323082 177 CGP 26797 WO 9323082 178 CGP 28727 WO 9323082 179 CGP 32413 WO 9323082 180 changrolin Sci. Sin. (Engl. Ed.) 22(10): 1220-8 (1979) 181 CHF-1521 (combination of delapril and manidipine) 182 cilnidipine U.S. Pat. No. 4,672,068 183 cinnarizine U.S. Pat. No. 3,799,934 184 civamide WO 9640079 U.S. Pat. No. 5,840,762 185 clentiazem/TA3090 EP 00127882 U.S. Pat. No. 4,567,175 186 clevidipine WO 9512578 187 CNS-1067 IDdb 211675 188 CNS-1237 Annals of the New York Academy of Sciences, 765 (Neuroprotective Agents): 210- 29 (1995) 189 CNS-2103 (from spider venom) WO 9214709 A2 190 COR 28-22 WO 9323082 191 COR 2707C WO 9323082 192 COR 3752C WO 9323082 193 CP-060S WO 9500471 A1 194 CPC-301 IDdb 231888 195 CPC 304 IDdb 185705 196 CPC-317 IDdb 185700 197 CPU 23 Yaoxue Xuebao, 25(11): 815-23 (1990) CAN 114: 143097 198 CPU-86017 EP 00538844 199 CRE 202 WO 9323082 200 CRE 204 WO 9323082 201 CRE 1005 WO 9323082 202 CRL-42752 WO 00003987 203 cronidipine (LF 2-0254) EP 240398 A1 204 CV 159 FR 2511370 A1 205 D-2024 (verapamil(S)) WO 09509150 206 D 2603 WO 9323082 207 dagapamil WO 9323082 EP 64158 A1 208 darodipine PY108068 EP 00000150 209 dauricine NSC 36413 Acta Pharmacologica Sinica 7(6): 543-7 (1986) 210 desmethyl verapamil 211 DHM 9 WO 8604581 A1 212 DHP 218/PAK 9 EP 00121117 213 diclofurime DE 79-29227999 214 dihydropyridine calcium Journal of Medicinal Chemistry channel blockers 41(4): 509-514 (1998) 215 diltiazem U.S. Pat. No. 3,562,257 216 diperdipine EP 00218996 217 dipfluzine DE 3318577 A1 218 diproteverine BRL 40015 BE 866208 219 dopropidil EP 00031771 220 dotarizine/FI 6026 U.S. Pat. No. 4,883,797 221 DTZ-323 Molecular Pharmacology, 51(2): 262-268 (1997) 222 E-2050 JP 2001199949 A2 223 E4080 EP 344577 A2 224 efonidipine hydrochloride U.S. Pat. No. 4,885,284 225 EG 1088 EP 56637 A1 226 EGIS 3966 DE 4027052 A1 227 eglodipine DE 3825962 A1 228 emopamil (racemic) SZ 45 DE 3344755 A1 229 (S)-emopamil DE 3344755 A1 230 enalapril_nitrendipine, Vita- EP 00884054 Inveest 231 etafenonee LG 11457 DE 1265758 232 ethosuximide 233 eugenodilol JP 11255719 A2 234 evodiamine JP 52077098 235 F-0401 EP 00320984 236 falipamil AQA 39 Journal of Medicinal Chemistry, 33(5): 1496-504 (1990) 237 fantofarone SR 33557 EP 235111 A1 U.S. Pat. No. 4,957,925 238 fasudil (iv formulation), Asahi U.S. Pat. No. 4,678,783 239 FCE-24265 EP 373645 A1 240 FCE-26262 241 FCE-27335 242 FCE-27892 243 FCE-28718 EP 00755931 244 fedopamil 245 felodipine U.S. Pat. No. 4,264,611 246 felodipine + ramipril WO 09607400 (Astra/Aventis) 247 fendiline U.S. Pat. No. 3,262,977 248 feniline 249 flezelastine, D 18024 EP 590551 A2 250 flordipine 251 fluodipine U.S. Pat. No. 3,773,939 252 fluphenazine, S94 Journal of Medicinal Chemistry, SQ 4918 19(6): 850-2 (1976) Triflumethazine Vespazine 253 fostedil KB944 EP 10120 254 FPL 62129 EP 125803 A2 255 FR 46171 256 FR-172516 JP 09040647 257 FRC 9411 258 FRG 8653 259 FRG-8701 260 furaldipine 261 furnidipine (CRE 319) Journal of Medicinal Chemistry, 38(15): 2830-41 (1995) 262 GOE 5057 263 GOE 5584 A EP 173933 A1 264 GOE 93007 265 GR 60139 266 GR 55234A (R-enantiomer of Haemotalogica, 79(4): 328-33 telupidine) (1994) 267 GR 55235A (L-enantiomer of Haemotalogica, 79(4): 328-33 telupidine) (1994) 268 GS-386 269 GYKI 46544 270 H32438 271 HA 22 U.S. Pat. No. 5,240,947 272 HA 23 U.S. Pat. No. 5,240,947 273 HA 1004 274 GA 1077 275 HE 30346 276 HNS 32 JP 08311007 A2 277 HOE 166 Molecular Pharmacology 33(4): 363-9 (1988) 278 HOE 263 279 HP 406 U.S. Pat. No. 4,521,537 280 ICI 206970 EP 293170 A1 19881130 281 iganidipine JP 63225355 A2 19880920 282 IHC 72 Acta Pharmaceutica Sinica, 27(6): 407-11 (1992) 283 ipenoxazone 284 isradipine U.S. Pat. No. 4,466,972 285 JTV-519 WO 09212148 286 KB 2796 287 KP-840 Yakubutsu, Seishin, Kodo, 12(6): 353 (1992) 288 KP 873 289 KT-362 Archiv Der Pharmazie, 328(4): 313-6 (1995) 290 KT 2230 General Pharmacology, 22(3): 443-8 (1991) 291 KW 3049 (see benipidine) 292 L-366682 EP 00444898 293 L-651582 294 L 735821 WO 9514471 A1 19950601 British Journal of Pharmacology, 132(1): 101-110 (2001) 295 lacidipine GR 43659 Sn305 U.S. Pat. No. 4,801,599 DE 03529997 296 LAS 30356 297 LAS 30398 298 LAS 30538 Journal of Pharmacy and Pharmacology, 44(10: 830-5 (1992) 299 LAS Z077 300 LCB-2514 301 lemildipine P 59152373 A2 302 lercanidipine U.S. Pat. No. 4,705,797 303 leualacin EP 00358418 304 levosemotiadil SA 3212 WO 08700838 305 lidoflazine R7904 U.S. Pat. No. 3,267,104 306 lifarizine RS 87476 U.S. Pat. No. 0,435,417 307 LOE-908 308 lomerizine KB 2796 U.S. Pat. No. 4,663,325 EP 00158566 309 LU 49700 (main metabolite of DE 3642331 A1 gallopamil) 310 LU 49938 311 LY-042826 European Journal of Pharmacology, 408(3): 241-248 (2000) 312 LY-393615 European Journal of Pharmacology, 408(3): 241-248 (2000) 313 manidipine/CV U.S. Pat. No. 4,892,875 4093/franidipine EP 00094159 314 MCI 176 (MY7674) EP 169537 A2 315 McN 5691 (see RWJ 26240) 316 McN-6186 317 MCN 6497 318 MD 260792 319 MDL 143 320 MDL 12330A 321 MDL 16582A WO 9323082 322 MDL 72567 GB 2137622 A1 19841010 CAN 102: 95548 323 MEM 1003/nimopidine analog/BAY Z 4406 324 mepirodipine 325 mesudipine 326 mibefradil EP 00268148 U.S. Pat. No. 4,808,605 327 minodipine 328 mioflazine 329 MJ 14712 330 monatepil maleate (AD 2615) WO 08601203 U.S. Pat. No. 4,749,703 331 MPC 1304 332 MPC 2101 FR 2514761 A1 333 MR-14134 Pharmacology, 51(2): 84-95 (1995) 334 N-3601 EP 254322 A1 335 N 20776 336 N-allyl secoboldine 337 naltiazem Ro 23-6152 U.S. Pat. No. 4,652,561 338 NB 818 339 NC 1100 340 NC O 700 341 NCC 09-0026 342 nexopamil EP 00271013 343 NH 2250 344 NH 2716 345 nicainoprol RU 42924 DE 2934609 346 nicardipine (nifelan) U.S. Pat. No. 3,985,847 347 nictiazem 348 nifedipine U.S. Pat. No. 3,485,847 349 nigulipine WO 8807525 A1 350 niludipine 351 nilvadipine FK 235 U.S. Pat. No. 4,338,322 DE 02940833 352 nimodipine U.S. Pat. No. 3,842,096 353 misoldipine Bay y 5552 U.S. Pat. No. 4,154,839 354 nitrendipine Bay k 5009 U.S. Pat. No. 3,799,934 355 NMDA/calcium channel WO 09745115 antagonists, Allelix 356 NKY 722 357 NMED 126 (MC-34D) WO 0145709 A1 U.S. Pat. No. 6,387,897 358 NMED 427 WO 0145709 A1 U.S. Pat. No. 6,387,897 359 NMED 724 WO 0145709 A1 U.S. Pat. No. 6,387,897 360 NMED 826 WO 0145709 A1 U.S. Pat. No. 6,387,897 361 NMED JM-G-10 WO 0145709 A1 U.S. Pat. No. 6,387,897 362 NMED 157 39-1B4 WO 0145709 A1 U.S. Pat. No. 6,387,897 363 NMED 160 39-45-3 WO 0145709 A1 U.S. Pat. No. 6,387,897 364 NNC-09-0026 WO 9201672 365 NP 252 Life Sciences, 48(2): 183-8 (1991) 366 NS 626 367 NS-638 U.S. Pat. No. 5,314,903 EP 545845 A1 368 NS-649 EP 520200 A2 369 NS-696 370 NS-7 WO 09607641 371 NS 3034 372 NZ 105 373 olradipine S 11568 FR 2602231 A1 374 ONO-2921 WO 0000470 A1 375 OPC 13340 376 OPC 88117 EP 236140 A2 377 ORG 13020 378 Org-13061 Fundamental & Clinical Pharmacology, 11(5): 416-426 (1997) 379 OSAT (nifedipine) 380 osthole JP 47000430 381 oxodipine IQB 837V ES 531033 A1 382 P 0825 383 P 1268 384 palonidipine hydrochloride Ep 128010 A2 385 PCA-50922 386 PCA-50938 Brain Research 772(1, 2): 57-62 (1997) 387 PCA-50941 388 PCA 50982 389 PD-0204318 WO 9943658 A1 390 PD-029361 IDdb 300520 391 PD 122860 Ep 206747 A2 392 PD 151307 U.S. Pat. No. 6,423,689 J. Med. Chem. 43: 3472 (2000) 393 PD-157667 U.S. Pat. No. 5,767,129 394 PD-158143 WO 9705125 A1 395 PD 173212 396 PD 175069 WO 9854123 A1 397 PD 176078 WO 9955688 J. Med. Chem. 43: 3474 (2000) 398 PD 181283 Bioorganic & Medicinal Chemistry Letters, 9(16): 2453- 2458 (1999) 399 pelanserin 400 perhexiline GB 1025578 401 petrosynol Tetrahedron, 49(45): 10435-8 (1993) 402 PF 244 403 PFS 1144 (EO 122) DE 2802208 404 pirmenol U.S. Pat. No. 4,112,103 405 pirprofurol 406 407 PN 200110 408 PNU 156654E WO 9705102 A1 409 pranidipine EP 00145434 410 prenylamine 411 propiverine DD 106643 412 ptilomycalin AM 413 QM 96233 414 QM 96159 415 QM 96127 416 QX-314 Biophysical Journal, 27(1): 39- 55 (1979) 417 R 56865 EP 184257 A1 418 R 59494 Ep 184257 A1 419 R 71811 420 Rec 152288 421 Rec 152375, Rec 15/375 422 RGH-2716 (TDN 345) EP 414421 A2 423 RGH 2970 424 riodipine 425 Ro-11-2933 EP 00523493 426 Ro 18-3981 427 Ro 40-5967 428 RO 445912 dithiane Biochemical Pharmacology, derivatives of tiapamil 50(2): 187-96 (1995) 429 ronipamil 430 RS-5773 EP 00353032 431 RS 93007 432 RS 93522 U.S. Pat. No. 4,595,690 433 RU-43945 WO 9323082 A1 434 RWJ-22108 U.S. Pat. No. 04,845,225 435 RWJ-22726 U.S. Pat. No. 04,845,225 436 RWJ 26240 McN 5691 EP 146721 A2 437 RWJ 26899 EP 237191 A1 438 RJW-26902 439 RWJ-29009 EP 00493048 440 RWJ-37868 WO 0048584 441 ryanodine 442 S-(−)-amlodipine 443 S 11568 444 S 12967 ZA 9000231 A 445 S-12968 EP 00406502 446 S-2150 Ep 00615971 447 S-312-d JP 03052890 448 S 830327 449 SA 2572 JP 63104969 A2 450 SA 2995 451 SA 3212 452 sabeluzole Ep 184257 A1 453 safinamide EP 400495 A1 454 sagandipine 455 salicylaldoxime Clinical and Experimental Pharmacology and Physiology 26(12): 964-9 (1999) 456 SANK-71996 457 SB-201823A WO 09202502 458 SB-206284A 459 SB 221420A WO 9002494 A1 460 SB-237376 WO 0209761 A2 461 SB 262470 WO 0183546 A1 462 SC 30552 463 SDZ-249482 464 selodipine 465 semotiadil (SD 3211) U.S. Pat. No. 4,786,635 JP 09012576 466 SIM 6080 Ep 293925 A2 467 sipatrigine EP 372934 A2 468 sinomenine (active from a WO 0269971 A1 Chinese medicinal plant) 469 siratiazem WO 09117153 470 SKF-45675 471 SKF-96365 European Journal of Pharmacology 188(6): 417-21 (1990) 472 SKT-M-26 473 SL-34.0829 WO 0209761 A2 474 SL 651708 475 SL 851016 476 SL-870495 477 SM-6586 EP 00177965 478 SNX-124 479 SNX 185 WO 9310145 A1 480 SNX-236 WO 09313128 481 SNX-239 Pain, 60(1): 83-90 (1995) 482 SNX-483 (peptides from WO 9805780 A2 tarantula venom) 483 sornidipine 484 SQ 31486 EP 205334 A2 485 SQ 31727 486 SQ 31765 487 SQ 32321 488 SQ 32324 489 SQ 32547 EP 400665 A2 490 SQ 32926 EP 400665 A2 491 SQ-33351 WO 09006118 492 SQ 33537 493 SQ 34399 494 SR-33805 EP 576347 A1 495 SUN 5647 496 SUN 6087 497 SUN-N8075 WO 9923072 A2 498 T-477 EP 00441539 499 TA-993 JP 01050872 500 taludipine 501 tamolarizine EP 00354068 502 TDN-345 503 Teczem 504 temiverine CAN 131: 193592 505 terflavoxate EP 72620 A1 506 terodiline TD 758 U.S. Pat. No. 3,371,014 507 tetrandrine Clinical and Experimental Pharmacology and Physiology, 23(8): 715-753 (1996) 508 TH-1177 509 TH-9229 WO 09607415 510 thapsigargin British Journal of Pharmacology, 95(3): 705-712 (1985) 511 tiapamil 512 tinctormine Chemical & Pharmaceutical Bulletin 40(12): 3355-7 (1992) 513 TJN 220 (O-ethylfangchinoline) JP 63179878 A2 514 TMB 8 Journal of Cell Science 79: 151- 160 (1985) 515 TN-871 European Journal of Pharmacology 342 (2/3): 167- 175 (1998) 516 TR 2957 517 trapidil 518 trimetazidine U.S. Pat. No. 3,262,852 519 TY-10835 Pharmacometrics, 1998, 54: 3 (153) 520 U-88999 WO 9204338 521 U-92032 WO 09204338 522 U-92798 WO 9204338 A1 523 UK 1745 EP 653426 A1 524 UK-51656 EP 00089167 525 UK 52831 JP 59118782 A2 526 UK 55444 EP 00132375 527 UK 56593 528 UK-84149 EP 404359 A1 529 ULAH 99 European Journal of Pharmacology, 229(1): 55-62 (1992) 530 vantanipidine EP 257616 A2 531 verapamil, verelan U.S. Pat. No. 3,261,859 532 S-verapamil, D-2024, WO 09509150 levoverapamil 533 vexibinol Sophoraflavanone G Chemical and Pharmaceutical Bulletin 38(4): 1039-44 (1990) 534 vinigrol 535 vintoperol RGH 2981 RT 303 WO 9207851 536 vingrol 537 vintoperol/RGH 2981/RT 303 WO 9207851 538 VUF-8929 EP 467435 A2 539 VULM 993 540 vantanipidine Ep 257616 A2 541 W 787 542 WAS 4206 543 WK 269 544 WY 27569 545 WY 44644 546 WY 44705 547 WY 46622 548 WY 47324 549 xanthonolol U.S. Pat. No. 5,495,005 550 Y 19638 551 Y-22516 WO 9323082 552 Y 208835 553 YC 114 554 YH-334 EP 00366548 555 YM 15430-1 (see YM 430) 556 YM-16151-4 (YM 151) EP 00167371 557 YM-430 (YM 15430) WO 0209761 A2 558 YS 035 BE 897244 559 YS 161 560 Z-6568 Journal of Mass Spectrometry, 31(1): 37-46 (1996) 561 ziconotiide omega WO 9107980 conotoxin/MVIIA/SNX-111 562 ZM-224832 EP 00343865 563 zonisamide U.S. Pat. No. 4,172,896

Synthesis

The synthesis of charge-modified ion channel blockers may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of the parent ion channel blocker, the linker, the bulky group, and/or the charged group. For example, commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m-nitrophenyl. Other commonly used protecting groups for amines include amides, such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert-butylsulfonyl amides. Examples of commonly used protecting groups for carboxyls include esters, such as methyl, ethyl, tert-butyl, 9-fluorenylmethyl, 2-(trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho-esters, and halo-esters. Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P-nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy-trityls), and silyl ethers. Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls. In addition, sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides). Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule. The conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis (2^(nd) Ed.), John Wiley & Sons, 1991 and P. J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994.

Charge-modified ion channel blockers can be prepared using techniques familiar to those skilled in the art. The modifications can be made, for example, by alkylation of the parent ion channel blocker using the techniques described by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, John Wiley & Sons, Inc., 1992, page 617. The conversion of amino groups to guanidine groups can be accomplished using standard synthetic protocols. For example, Mosher has described a general method for preparing mono-substituted guanidines by reaction of aminoiminomethanesulfonic acid with amines (Kim et al., Tetrahedron Lett. 29:3183 (1988)). A more convenient method for guanylation of primary and secondary amines was developed by Bernatowicz employing 1H-pyrazole-1-carboxamidine hydrochloride; 1-H-pyrazole-1-(N,N′-bis(tert-butoxycarbonyl)carboxamidine; or 1-H-pyrazole-1-(N,N′-bis(benzyloxycarbonyl)carboxamidine. These reagents react with amines to give mono-substituted guanidines (see Bernatowicz et al., J. Org. Chem. 57:2497 (1992); and Bernatowicz et al., Tetrahedron Lett. 34:3389 (1993)). In addition, thioureas and S-alkyl-isothioureas have been shown to be useful intermediates in the syntheses of substituted guanidines (Poss et al., Tetrahedron Lett. 33:5933 (1992)). In certain embodiments, the guanidine is part of a heterocyclic ring having two nitrogen atoms (see, for example, the structures below). The ring system can include an alkylene or

alkenylene of from 2 to 4 carbon atoms, e.g., ring systems of 5, 6, and 7-membered rings. Such ring systems can be prepared, for example, using the methods disclosed by Schlama et al., J. Org. Chem. 62:4200 (1997).

Charge-modified ion channel blockers can be prepared by alkylation of an amine nitrogen in the parent compound as shown in Scheme 1.

Alternatively, charge-modified ion channel blockers can be prepared by introduction of a guanidine group. The parent compound can be reacted with a cynamide, e.g., methylcyanamide, as shown in Scheme 2 or pyrazole-1-carboxamidine derivatives as shown in Scheme 3 where Z is H or a suitable protecting group. Alternatively, the parent compound can be reacted with cyanogens bromide followed by reaction with methylchloroaluminum amide as shown in Scheme 4. Reagents such as 2-(methylthio)-2-imidazoline can also be used to prepare suitably functionalized derivatives (Scheme 5).

Any ion channel blocker containing an amine nitrogen atom (e.g., a compound selected from Compounds (1)-(563) or a compound according to Formulas (I)-(XIV)) can be modified as shown in Schemes 1-5.

TRPV1 Agonists

TRPV1 agonists that can be employed in the methods and kits of the invention include but are not limited to any that activates TRPV1 receptors on nociceptors and allows for entry of at least one inhibitor of voltage-gated ion channels. A suitable TRPV1 agonist is capsaicin or another capsaicinoids, which are members of the vanilloid family of molecules. Naturally occurring capsaicinoids are capsaicin itself, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, homocapsaicin, and nonivamide, whose structures are provided below.

Other suitable capsaicinoids and capsaicinoid analogs and derivatives for use in the compositions and methods of the present invention include naturally occurring and synthetic capsaicin derivatives and analogs including, e.g., vanilloids (e.g., N-vanillyl-alkanedienamides, N-vanillyl-alkanedienyls, and N-vanillyl-cis-monounsaturated alkenamides), capsiate, dihydrocapsiate, nordihydrocapsiate and other capsinoids, capsiconiate, dihydrocapsiconiate and other coniferyl esters, capsiconinoid, resiniferatoxin, tinyatoxin, civamide, N-phenylmethylalkenamide capsaicin derivatives, olvanil, N-[(4-(2-aminoethoxy)-3-methoxyphenyl)methyl]-9Z-octa-decanamide, N-oleyl-homovanillamide, triprenyl phenols (e.g., scutigeral), gingerols, piperines, shogaols, guaiacol, eugenol, zingerone, nuvanil, NE-19550, NE-21610, and NE-28345. Additional capsaicinoids, their structures, and methods of their manufacture are described in U.S. Pat. Nos. 7,446,226 and 7,429,673, which are hereby incorporated by reference.

Additional suitable TRPV1 agonists include but are not limited to eugenol, arvanil (N-arachidonoylvanillamine), anandamide, 2-aminoethoxydiphenyl borate (2APB), AM404, resiniferatoxin, phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), olvanil (NE 19550), OLDA (N-oleoyldopamine), N-arachidonyldopamine (NADA), 6′-iodoresiniferatoxin (6′-IRTX), C18 N-acylethanolamines, lipoxygenase derivatives such as 12-hydroperoxyeicosatetraenoic acid, inhibitor cysteine knot (ICK) peptides (vanillotoxins), piperine, MSK195 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-2-[4-(2-aminoethoxy)-3-methoxyphenyl]acetamide), JYL79 (N-[2-(3,4-dimethylbenzyl)-3-(pivaloyloxy)propyl]-N′-(4-hydroxy-3-methoxybenzyl)thiourea), hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 10-shogaol, oleylgingerol, oleylshogaol, and SU200 (N-(4-tert-butylbenzyl)-N′-(4-hydroxy-3-methoxybenzyl)thiourea).

Still other TRPV1 agonists include amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.

TRP1a Agonists

TRP1A agonists that can be employed in the methods and kits of the invention include any that activates TRP1A receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels. Suitable TRP1A agonists include but are not limited to cinnamaldehyde, allyl-isothiocynanate, diallyl disulfide, icilin, cinnamon oil, wintergreen oil, clove oil, acrolein, hydroxy-alpha-sanshool, 2-aminoethoxydiphenyl borate, 4-hydroxynonenal, methyl p-hydroxybenzoate, mustard oil, and 3′-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). Still other agonists include amylocaine, articaine, benzocaine, bupivacaine, carbocaine, carticaine, chloroprocaine, cyclomethycaine, dibucaine (cinchocaine), dimethocaine (larocaine), etidocaine, hexylcaine, levobupivacaine, lidocaine, mepivacaine, meprylcaine (oracaine), metabutoxycaine, piperocaine, prilocaine, procaine (novacaine), proparacaine, propoxycaine, risocaine, ropivacaine, tetracaine (amethocaine), and trimecaine.

P2X Agonists

P2X agonists that can be employed in the methods and kits of the invention include any that activates P2X receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels. Suitable P2X agonists include but are not limited to 2-methylthio-ATP, 2′ and 3′-O-(4-benzoylbenzoyl)-ATP, and ATP5′-O-(3-thiotriphosphate).

TRPM8 Agonists

TRPM8 agonists that can be employed in the methods and kits of the invention include any that activates TRPM8 receptors on nociceptors or pruriceptors and allows for entry of at least one inhibitor of voltage-gated ion channels. Suitable TRPM8 agonists include but are not limited to menthol, iciclin, eucalyptol, linalool, geraniol, and hydroxycitronellal.

Additional Agents

If desired, one or more additional biologically active agents typically used to treat neurogenic inflammation may be used in combination with a composition of the invention described herein. The biologically active agents include, but are not limited to, acetaminophen, NSAIDs, glucocorticoids, narcotics (e.g. opioids), tricyclic antidepressants, amine transporter inhibitors, anticonvulsants, antiproliferative agents, and immune modulators. The biologically active agents can be administered prior to, concurrent with, or following administration of a composition of the invention, using any formulation, dosing, or administration known in the art that is therapeutically effective.

Non-steroidal anti-inflammatory drugs (NSAIDs) that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, acetylsalicylic acid, amoxiprin, benorylate, benorilate, choline magnesium salicylate, diflunisal, ethenzamide, faislamine, methyl salicylate, magnesium salicylate, salicyl salicylate, salicylamide, diclofenac, aceclofenac, acemethacin, alclofenac, bromfenac, etodolac, indometacin, nabumetone, oxametacin, proglumetacin, sulindac, tolmetin, ibuprofen, alminoprofen, benoxaprofen, carprofen, dexibuprofen, dexketoprofen, fenbufen, fenoprofen, flunoxaprofen, flurbiprofen, ibuproxam, indoprofen, ketoprofen, ketorolac, loxoprofen, naproxen, oxaprozin, pirprofen, suprofen, tiaprofenic acid, mefenamic acid, flufenamic acid, meclofenamic acid, tolfenamic acid, phenylbutazone, ampyrone, azapropazone, clofezone, kebuzone, metamizole, mofebutazone, oxyphenbutazone, phenazone, sulfinpyrazone, piroxicam, droxicam, lornoxicam, meloxicam, tenoxicam, and the COX-2 inhibitors celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and pharmaceutically acceptable salts thereof.

Glucocorticoids that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, hydrocortisone, cortisone acetate, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisones acetate, deoxycorticosterone acetate, aldosterone, and pharmaceutically acceptable salts thereof.

Narcotics that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited, to tramadol, hydrocodone, oxycodone, morphine, and pharmaceutically acceptable salts thereof.

Antiproliferative and immune modulatory agents that can be administered to a patient (e.g., a human) suffering from neurogenic inflammation in combination with a composition of the invention include, but are not limited to, alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, dihydrofolate reductase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, TNF-alpha agonists, TNF-alpha antagonists or scavengers, interleukin 1 (IL-1) antagonists or scavengers, endothelin A receptor antagonists, retinoic acid receptor agonists, hormonal agents, antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

Formulation of Compositions

The administration of a combination of the invention may be by any suitable means that results in the reduction of inflammation at the target region (e.g., any inflamed tissue or mucosal surface). The inhibitor(s) of voltage-gated ion channels may be contained in any appropriate amount in any suitable carrier substance, and are generally present in amounts totaling 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is suitable for intraarticular, oral, parenteral (e.g., intravenous, intramuscular), rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, vaginal, intravesicular, intraurethral, intrathecal, epidural, aural, or ocular administration, or by injection, inhalation, or direct contact with the nasal, genitourinary, gastrointesitnal, reproductive or oral mucosa.

Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, preparations suitable for iontophoretic delivery, or aerosols. The compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A. R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York).

Each compound of a combination therapy, as described herein, may be formulated in a variety of ways that are known in the art. For example, the first and second agents of the combination therapy may be formulated together or separately. Desirably, the first and second agents are formulated together for the simultaneous or near simultaneous administration of the agents.

The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include, but are not limited to, kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, two topical creams, etc. The kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions.

The kit may be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”). The kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.

Controlled Release Formulations

Each compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be formulated for controlled release (e.g., sustained or measured) administration, as described in U.S. Patent Application Publication Nos. 2003/0152637 and 2005/0025765, each incorporated herein by reference. For example, a compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, can be incorporated into a capsule or tablet, that is administered to the site of inflammation.

Any pharmaceutically acceptable vehicle or formulation suitable for local infiltration or injection into a site to be treated (e.g., a painful surgical incision, wound, or joint), that is able to provide a sustained release of compound of the invention, alone or in combination with one or more of the biologically active agents as described herein, may be employed to provide for prolonged elimination or alleviation of inflammation, as needed. Slow release formulations known in the art include specially coated pellets, polymer formulations or matrices for surgical insertion or as sustained release microparticles, e.g., microspheres or microcapsules, for implantation, insertion, infusion or injection, wherein the slow release of the active medicament is brought about through sustained or controlled diffusion out of the matrix and/or selective breakdown of the coating of the preparation or selective breakdown of a polymer matrix. Other formulations or vehicles for sustained or immediate delivery of an agent to a preferred localized site in a patient include, e.g., suspensions, emulsions, gels, liposomes and any other suitable art known delivery vehicle or formulation acceptable for subcutaneous or intramuscular administration.

A wide variety of biocompatible materials may be utilized as a controlled release carrier to provide the controlled release of a compound of the invention, alone or in combination with one or more biologically active agents, as described herein. Any pharmaceutically acceptable biocompatible polymer known to those skilled in the art may be utilized. It is preferred that the biocompatible controlled release material degrade in vivo within about one year, preferably within about 3 months, more preferably within about two months. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50% of the material degrading into non-toxic residues, which are removed by the body, and 100% of the compound of the invention being released within a time period within about two weeks, preferably within about 2 days to about 7 days. A degradable controlled release material should preferably degrade by hydrolysis, either by surface erosion or bulk erosion, so that release is not only sustained but also provides desirable release rates. However, the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local anesthetic effect over the desired time period.

Suitable biocompatible polymers can be utilized as the controlled release material. The polymeric material may comprise biocompatible, biodegradable polymers, and in certain preferred embodiments is preferably a copolymer of lactic and glycolic acid. Preferred controlled release materials which are useful in the formulations of the invention include the polyanhydrides, polyesters, co-polymers of lactic acid and glycolic acid (preferably wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 i.e., 80% or less lactic acid to 20% or more glycolic acid by weight)) and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride. Examples of polyesters include polylactic acid, polyglycolic acid and polylactic acid-polyglycolic acid copolymers. Other useful polymers include protein polymers such as collagen, gelatin, fibrin and fibrinogen and polysaccharides such as hyaluronic acid.

The polymeric material may be prepared by any method known to those skilled in the art. For example, where the polymeric material is comprised of a copolymer of lactic and glycolic acid, this copolymer may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539, incorporated herein by reference. Alternatively, copolymers of lactic and glycolic acid may be prepared by any other procedure known to those skilled in the art. Other useful polymers include polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polyphosphoesters, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters or mixtures or blends of any of these. Pharmaceutically acceptable polyanhydrides which are useful in the present invention have a water-labile anhydride linkage. The rate of drug release can be controlled by the particular polyanhydride polymer utilized and its molecular weight. The polysaccharides may be poly-1,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof. The biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-1,4-glucan, including hydrolyzed amylopectin, hydroxyalkyl derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like. The polyanhydride polymer may be branched or linear. Examples of polymers which are useful in the present invention include (in addition to homopolymers and copolymers of poly(lactic acid) and/or poly(glycolic acid)) poly [bis(p-carboxyphenoxy) propane anhydride] (PCPP), poly[bis(p-carboxy)methane anhydride] (PCPM), polyanhydrides of oligomerized unsaturated aliphatic acids, polyanhydride polymers prepared from amino acids which are modified to include an additional carboxylic acid, aromatic polyanhydride compositions, and co-polymers of polyanhydrides with other substances, such as fatty acid terminated polyanhydrides, e.g., polyanhydrides polymerized from monomers of dimers and/or trimers of unsaturated fatty acids or unsaturated aliphatic acids. Polyanhydrides may be prepared in accordance with the methods set forth in U.S. Pat. No. 4,757,128, incorporated herein by reference. Polyorthoester polymers may be prepared, e.g., as set forth in U.S. Pat. No. 4,070,347, incorporated herein by reference. Polyphosphoesters may be prepared and used as set forth in U.S. Pat. Nos. 6,008,318, 6,153,212, 5,952,451, 6,051,576, 6,103,255, 5,176,907 and 5,194,581, each of which is incorporated herein by reference.

Proteinaceous polymers may also be used. Proteinaceous polymers and their soluble derivatives include gelation biodegradable synthetic polypeptides, elastin, alkylated collagen, alkylated elastin, and the like. Biodegradable synthetic polypeptides include poly-(N-hydroxyalkyl)-L-asparagine, poly-(N-hydroxyalkyl)-L-glutamine, copolymers of N-hydroxyalkyl-L-asparagine and N-hydroxyalkyl-L-glutamine with other amino acids. Suggested amino acids include L-alanine, L-lysine, L-phenylalanine, L-valine, L-tyrosine, and the like.

In additional embodiments, the controlled release material, which in effect acts as a carrier for a compound of the invention, alone or in combination with one or more biologically active agents as described herein, can further include a bioadhesive polymer such as pectins (polygalacturonic acid), mucopolysaccharides (hyaluronic acid, mucin) or non-toxic lectins or the polymer itself may be bioadhesive, e.g., polyanhydride or polysaccharides such as chitosan.

In embodiments where the biodegradable polymer comprises a gel, one such useful polymer is a thermally gelling polymer, e.g., polyethylene oxide, polypropylene oxide (PEO-PPO) block copolymer such as Pluronic™ F127 from BASF Wyandotte. In such cases, the local anesthetic formulation may be injected via syringe as a free-flowing liquid, which gels rapidly above 30° C. (e.g., when injected into a patient). The gel system then releases a steady dose of a compound of the invention, alone or in combination with one or more biologically active agents as described herein, at the site of administration.

Solid Dosage Forms for Oral Use

Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

Two or more compounds may be mixed together in a tablet, capsule, or other vehicle, or may be partitioned. In one example, the first compound is contained on the inside of the tablet, and the second compound is on the outside, such that a substantial portion of the second compound is released prior to the release of the first compound.

Formulations for oral use may also be provided as chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders, granulates, and pellets may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

Dissolution or diffusion controlled release can be achieved by appropriate coating of a tablet, capsule, pellet, or granulate formulation of compounds, or by incorporating the compound into an appropriate matrix. A controlled release coating may include one or more of the coating substances mentioned above and/or, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels, 1,3 butylene glycol, ethylene glycol methacrylate, and/or polyethylene glycols. In a controlled release matrix formulation, the matrix material may also include, e.g., hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbon.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Generally, when administered to a human, the oral dosage of any of the compounds of the combination of the invention will depend on the nature of the compound, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day. Dosages up to 200 mg per day may be necessary.

Administration of each drug in a combination therapy, as described herein, can, independently, be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be indicated in many cases.

Topical Formulations

A composition of the invention, alone or in combination with one or more of the biologically active agents described herein, can also be adapted for topical use with a topical vehicle containing from between 0.0001% and 25% (w/w) or more of active ingredient(s).

In a preferred combination, the active ingredients are preferably each from between 0.0001% to 10% (w/w), more preferably from between 0.0005% to 4% (w/w) active agent. The cream can be applied one to four times daily, or as needed.

Performing the methods described herein, the topical vehicle containing the composition of the invention, or a combination therapy containing a composition of the invention is preferably applied to the site of inflammation on the patient. For example, a cream may be applied to the hands of a patient suffering from arthritic fingers.

Formulations for Nasal and Inhalation Administration

The pharmaceutical compositions of the invention can be formulated for nasal or intranasal administration. Formulations suitable for nasal administration, when the carrier is a solid, include a coarse powder having a particle size, for example, in the range of approximately 20 to 500 microns which is administered by rapid inhalation through the nasal passage. When the carrier is a liquid, for example, a nasal spray or as nasal drops, one or more of the formulations can be admixed in an aqueous or oily solution, and inhaled or sprayed into the nasal passage.

For administration by inhalation, the active ingredient can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount, Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

EXAMPLES

The following example is intended to illustrate the invention, and is not intended to limit it.

Example 1: Treatment of Neurogenic Inflammation with Intravenous Injection of QX-314

FIG. 1 is a graph showing the effect of intravenous QX-314 (0.4 mg/kg) on the edema elicited by injection of complete Freund's adjuvant (CFA) in the rat hindpaw determined by measuring the total volume of the hindpaw by plethysmography. The degree of swelling produced by injection of CFA is reduced by administration of QX-314 reflecting reduction in neurogenic edema resulting from the blockade of nociceptors by QX314. QX-314 by itself has no effect different from administration of saline.

Example 2: Entry of N-methyl-verapamil into Dorsal Root Ganglion Neurons Through Capsaicin-Activated TRPV1 Channels

N-methyl-verapamil, a charged derivative of the known calcium channel blocker verapamil and structurally related to D-890, can be loaded into dorsal root ganglion neurons through activation of TRPV1 channels by capsaicin. The internally-loaded N-methyl-verapamil then produces long-lasting inhibition of the voltage-dependent calcium channels in the neurons. Entry of the drug into the cell, and its blocking action, depends on applying the drug in the presence of capsaicin to activate the TRPV1 channels present in the neuronal membrane.

As shown in FIG. 2, the inhibition of voltage-dependent calcium channel current in a DRG neuron by N-methyl-verapamil applied in the presence of capsaicin to open TRPV1 channels. The traces show currents through voltage-activated calcium channels in a dissociated rat dorsal root ganglion neuron, recorded in whole-cell mode. Current was carried by 2 mM Ba²⁺ on a background of 155 mM N-methyl-D-glucamine (to eliminate Na current), with an internal CsCl-based solution. Calcium channels were opened by a voltage step from −80 mV to −20 mV. When channels are opened, inward-going current is carried by Ba²⁺ ions flowing into the cell.

Each panel shows calcium channel currents before and 3 minutes after exposure of the cell to either 1 μM capsaicin alone (top panel), 300 μM N-methyl-verapamil alone (middle panel), or 300 μM N-methyl-verapamil applied in the presence of 1 μM capsaicin to open TRPV1 channels (bottom panel). Control experiments using either capsaicin alone or N-methyl-verapamil alone each produce weak, transient effects that are rapidly reversed when the agents are washed away. The combination, however, produces an inhibition of calcium channel currents that persists after washout of the agents, consistent with N-methyl-verapamil having entered through TRPV1 channels and remaining trapped inside the cells, blocking the calcium channels from the inside.

Other Embodiments

Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific desired embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the fields of medicine, immunology, pharmacology, endocrinology, or related fields are intended to be within the scope of the invention.

All publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication was specifically and individually incorporated by reference. 

What is claimed is: 1-46. (canceled)
 47. A quaternary amine derivative of compound 51:

or salt thereof.
 48. A pharmaceutical composition comprising the compound of claim 47 and a pharmaceutically acceptable excipient.
 49. A method of treating a neurogenic inflammatory disorder in a human patient, the method comprising administering a therapeutically effective amount of the compound of claim 47 to the patient.
 50. The method of claim 49, wherein the neurogenic inflammatory disorder is selected from asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, pancreatitis, chronic cough, diabetes, rheumatic disease, eczema, cystitis, gastritis, urethritis, migraine headache, psoriasis, sinusitis, chronic rhinosinusitis, traumatic brain injury, sepsis, polymicrobial sepsis, tendinopathy, chronic urticaria, rosacea, sunburn, inhaled tear gases, acute lung injury, inhalation of irritants, inhalation of pollutants, and exposure to chemical warfare agents.
 51. A kit comprising the compound of claim 47 and instructions for administering the compound to a patient to treat neurogenic inflammation.
 52. A quaternary amine derivative of compound 70:

or salt thereof.
 53. A pharmaceutical composition comprising the compound of claim 52 and a pharmaceutically acceptable excipient.
 54. A method of treating a neurogenic inflammatory disorder in a human patient, the method comprising administering a therapeutically effective amount of the compound of claim 52 to the patient.
 55. The method of claim 54, wherein the neurogenic inflammatory disorder is selected from asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, pancreatitis, chronic cough, diabetes, rheumatic disease, eczema, cystitis, gastritis, urethritis, migraine headache, psoriasis, sinusitis, chronic rhinosinusitis, traumatic brain injury, sepsis, polymicrobial sepsis, tendinopathy, chronic urticaria, rosacea, sunburn, inhaled tear gases, acute lung injury, inhalation of irritants, inhalation of pollutants, and exposure to chemical warfare agents.
 56. A kit comprising the compound of claim 52 and instructions for administering the compound to a patient to treat neurogenic inflammation.
 57. A quarternary amine derivative of compound 86:

or salt thereof.
 58. A pharmaceutical composition comprising the compound of claim 57 and a pharmaceutically acceptable excipient.
 59. A method of treating a neurogenic inflammatory disorder in a human patient, the method comprising administering a therapeutically effective amount of the compound of claim 57 to the patient.
 60. The method of claim 59, wherein the neurogenic inflammatory disorder is selected from asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, pancreatitis, chronic cough, diabetes, rheumatic disease, eczema, cystitis, gastritis, urethritis, migraine headache, psoriasis, sinusitis, chronic rhinosinusitis, traumatic brain injury, sepsis, polymicrobial sepsis, tendinopathy, chronic urticaria, rosacea, sunburn, inhaled tear gases, acute lung injury, inhalation of irritants, inhalation of pollutants, and exposure to chemical warfare agents.
 61. A kit comprising the compound of claim 57 and instructions for administering the compound to a patient to treat neurogenic inflammation.
 62. A quarternary amine derivative of compound 95:

or salt thereof.
 63. A pharmaceutical composition comprising the compound of claim 62 and a pharmaceutically acceptable excipient.
 64. A method of treating a neurogenic inflammatory disorder in a human patient, the method comprising administering a therapeutically effective amount of the compound of claim 62 to the patient.
 65. The method of claim 64, wherein the neurogenic inflammatory disorder is selected from asthma, rhinitis, conjunctivitis, arthritis, colitis, contact dermatitis, pancreatitis, chronic cough, diabetes, rheumatic disease, eczema, cystitis, gastritis, urethritis, migraine headache, psoriasis, sinusitis, chronic rhinosinusitis, traumatic brain injury, sepsis, polymicrobial sepsis, tendinopathy, chronic urticaria, rosacea, sunburn, inhaled tear gases, acute lung injury, inhalation of irritants, inhalation of pollutants, and exposure to chemical warfare agents.
 66. A kit comprising the compound of claim 62 and instructions for administering the compound to a patient to treat neurogenic inflammation. 